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  • RESEARCH ARTICLE
    Yingfeng Zheng, Xiuxing Liu, Wenqing Le, Lihui Xie, He Li, Wen Wen, Si Wang, Shuai Ma, Zhaohao Huang, Jinguo Ye, Wen Shi, Yanxia Ye, Zunpeng Liu, Moshi Song, Weiqi Zhang, Jing-Dong J. Han, Juan Carlos Izpisua Belmonte, Chuanle Xiao, Jing Qu, Hongyang Wang, Guang-Hui Liu, Wenru Su
    Protein & Cell, 2020, 11(10): 740-770. https://doi.org/10.1007/s13238-020-00762-2

    Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtypespecific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.

  • REVIEW
    Chao Xu, Jinrong Min
    Protein & Cell, 2011, 2(3): 202-214. https://doi.org/10.1007/s13238-011-1018-1

    The WD40 domain exhibits a β-propeller architecture, often comprising seven blades. The WD40 domain is one of the most abundant domains and also among the top interacting domains in eukaryotic genomes. In this review, we will discuss the identification, definition and architecture of the WD40 domains. WD40 domain proteins are involved in a large variety of cellular processes, in which WD40 domains function as a protein-protein or protein-DNA interaction platform. WD40 domain mediates molecular recognition events mainly through the smaller top surface, but also through the bottom surface and sides. So far, no WD40 domain has been found to display enzymatic activity. We will also discuss the different binding modes exhibited by the large versatile family of WD40 domain proteins. In the last part of this review, we will discuss how post-translational modifications are recognized by WD40 domain proteins.

  • REVIEW
    Jun Ma
    Protein & Cell, 2011, 2(11): 879-888. https://doi.org/10.1007/s13238-011-1101-7

    Transcriptional activators are required to turn on the expression of genes in a eukaryotic cell. Activators bound to the enhancer can facilitate either the recruitment of RNA polymerase II to the promoter or its elongation. This article examines a few selected issues in understanding activator functions and activation mechanisms.

  • RESEARCH ARTICLE
    Kuisheng Liu, Xiaocui Xu, Dandan Bai, Yanhe Li, Yalin Zhang, Yanping Jia, Mingyue Guo, Xiaoxiao Han, Yingdong Liu, Yifan Sheng, Xiaochen Kou, Yanhong Zhao, Jiqing Yin, Sheng Liu, Jiayu Chen, Hong Wang, Yixuan Wang, Wenqiang Liu, Shaorong Gao
    Protein & Cell, 2023, 14(4): 262-278. https://doi.org/10.1093/procel/pwac029

    Self-organized blastoids from extended pluripotent stem (EPS) cells possess enormous potential for investigating postimplantation embryo development and related diseases. However, the limited ability of postimplantation development of EPS-blastoids hinders its further application. In this study, single-cell transcriptomic analysis indicated that the “trophectoderm (TE)-like structure” of EPS-blastoids was primarily composed of primitive endoderm (PrE)-related cells instead of TE-related cells. We further identified PrE-like cells in EPS cell culture that contribute to the blastoid formation with TE-like structure. Inhibition of PrE cell differentiation by inhibiting MEK signaling or knockout of Gata6 in EPS cells markedly suppressed EPS-blastoid formation. Furthermore, we demonstrated that blastocyst-like structures reconstituted by combining the EPS-derived bilineage embryo-like structure (BLES) with either tetraploid embryos or tetraploid TE cells could implant normally and develop into live fetuses. In summary, our study reveals that TE improvement is critical for constructing a functional embryo using stem cells in vitro.

  • RESEARCH ARTICLE
    Dan Tong, Li Zhang, Fei Ning, Ying Xu, Xiaoyu Hu, Yan Shi
    Protein & Cell, 2020, 11(2): 108-123. https://doi.org/10.1007/s13238-019-00662-0

    Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vitro.

  • RESEARCH ARTICLE
    Zezhong Liu, Wei Xu, Zhenguo Chen, Wangjun Fu, Wuqiang Zhan, Yidan Gao, Jie Zhou, Yunjiao Zhou, Jianbo Wu, Qian Wang, Xiang Zhang, Aihua Hao, Wei Wu, Qianqian Zhang, Yaming Li, Kaiyue Fan, Ruihong Chen, Qiaochu Jiang, Christian T. Mayer, Till Schoofs, Youhua Xie, Shibo Jiang, Yumei Wen, Zhenghong Yuan, Kang Wang, Lu Lu, Lei Sun, Qiao Wang
    Protein & Cell, 2022, 13(9): 655-675. https://doi.org/10.1007/s13238-021-00871-6

    New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design. Here, we identified a receptor-binding domain (RBD)-binding antibody, XG014, which potently neutralizes β-coronavirus lineage B (β-CoV-B), including SARS-CoV-2, its circulating variants, SARS-CoV and bat SARSr-CoV WIV1. Interestingly, antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibody-dependent SARS-CoV-2 spike (S) protein-mediated cell-cell fusion, suggesting a unique mode of recognition by XG014. Structural analyses reveal that XG014 recog-nizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional “down” conformation, while its family member XG005 directly competes with ACE2 binding and position the RBD “up”. Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo. Our findings suggest the potential to develop XG014 as pan-β-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines against β-CoV-B and newly emerging SARS-CoV-2 variants of concern.

  • RESEARCH ARTICLE
    Ning Hao,Yutao Chen,Ming Xia,Ming Tan,Wu Liu,Xiaotao Guan,Xi Jiang,Xuemei Li,Zihe Rao
    Protein & Cell, 2015, 6(2): 101-116. https://doi.org/10.1007/s13238-014-0126-0

    Human noroviruses (huNoVs) recognize histo-blood group antigens (HBGAs) as attachment factors, in which genogroup (G) I and GII huNoVs use distinct binding interfaces. The genetic and evolutionary relationships of GII huNoVs under selection by the host HBGAs have been well elucidated via a number of structural studies; however, such relationships among GI NoVs remain less clear due to the fact that the structures of HBGA-binding interfaces of only three GI NoVs with similar binding profiles are known. In this study the crystal structures of the P dimers of a Lewis-binding strain, the GI.8 Boxer virus (BV) that does not bind the A and H antigens, in complex with the Lewis b (Leb) and Ley antigens, respectively, were determined and compared with those of the three previously known GI huNoVs, i.e. GI.1 Norwalk virus (NV), GI.2 FUV258 (FUV) and GI.7 TCH060 (TCH) that bind the A/H/Le antigens. The HBGA binding interface of BV is composed of a conserved central binding pocket (CBP) that interacts with the β-galactose of the precursor, and a well-developed Le epitope-binding site formed by five amino acids, including three consecutive residues from the long P-loop and one from the S-loop of the P1 subdomain, a feature that was not seen in the other GI NoVs. On the other hand, the H epitope/acetamido binding site observed in the other GI NoVs is greatly degenerated in BV. These data explain the evolutionary path of GI NoVs selected by the polymorphic human HBGAs. While the CBP is conserved, the regions surrounding the CBP are flexible, providing freedom for changes. The loss or degeneration of the H epitope/acetamido binding site and the reinforcement of the Le binding site of the GI.8 BV is a typical example of such change selected by the host Lewis epitope.

  • RESEARCH ARTICLE
    Pingping Song,Shanshan Li,Hao Wu,Ruize Gao,Ruize Gao,Guanhua Rao,Dongmei Wang,Ziheng Chen,Biao Ma,Hongxia Wang,Nan Sui,Haiteng Deng,Zhuohua Zhang,Tieshan Tang,Zheng Tan,Zehan Han,Tieyuan Lu,Yushan Zhu,Quan Chen
    Protein & Cell, 2016, 7(2): 114-129. https://doi.org/10.1007/s13238-015-0230-9

    Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson’s disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.

  • LETTER
    Juan Zhang, Dingfeng Li, Keqiang He, Qiang Liu, Zhongwen Xie
    Protein & Cell, 2024, 15(2): 149-155. https://doi.org/10.1093/procel/pwad041
  • Research articles
    Youshang Zhang,
    Protein & Cell, 2010, 1(6): 507-509. https://doi.org/10.1007/s13238-010-0074-2
  • Research articles
    Songling Zhang, Wei Wu, Yanfang Wu, Jiyan Zheng, Talin Suo, Hong Tang, Jie Tang,
    Protein & Cell, 2010, 1(7): 656-663. https://doi.org/10.1007/s13238-010-0083-1
    RING finger protein 152 (RNF152) is a novel RING finger protein and has not been well characterized. We report here that RNF152 is a canonical RING finger protein and has E3 ligase activity. It is polyubiqitinated partly through Lys-48-linked ubiquitin chains in vivo and this phenomenon is dependent on its RING finger domain and transmembrane domain. RNF152 is localized in lysosomes and co-localized with LAMP3, a lysosome marker. Moreover, over-expression of RNF152 in Hela cells induces apoptosis. These results suggest that RNF152 is a lysosome localized E3 ligase with pro-apoptotic activities. It is the first E3 ligase identified so far that is involved in lysosome-related apoptosis.
  • REVIEW
    Xin Shao, Xiaoyan Lu, Jie Liao, Huajun Chen, Xiaohui Fan
    Protein & Cell, 2020, 11(12): 866-880. https://doi.org/10.1007/s13238-020-00727-5

    For multicellular organisms, cell-cell communication is essential to numerous biological processes. Drawing upon the latest development of single-cell RNA-sequencing (scRNA-seq), high-resolution transcriptomic data have deepened our understanding of cellular phenotype heterogeneity and composition of complex tissues, which enables systematic cell-cell communication studies at a single-cell level. We first summarize a common workflow of cell-cell communication study using scRNA-seq data, which often includes data preparation, construction of communication networks, and result validation. Two common strategies taken to uncover cell-cell communications are reviewed, e.g., physically vicinal structure-based and ligand-receptor interaction-based one. To conclude, challenges and current applications of cell-cell communication studies at a single-cell resolution are discussed in details and future perspectives are proposed.

  • REVIEW
    Peng Jiang,Wenjing Du,Mian Wu
    Protein & Cell, 2014, 5(8): 592-602. https://doi.org/10.1007/s13238-014-0082-8

    Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.

  • REVIEW
    Mark Bartlam, Tadashi Yamamoto
    Protein & Cell, 2010, 1(5): 443-452. https://doi.org/10.1007/s13238-010-0060-8

    The CCR4-NOT complex is a highly conserved, multifunctional machinery controlling mRNA metabolism. Its components have been implicated in several aspects of mRNA and protein expression, including transcription initiation, elongation, mRNA degradation, ubiquitination, and protein modification. In this review, we will focus on the role of the CCR4-NOT complex in mRNA degradation. The complex contains two types of deadenylase enzymes, one belonging to the DEDD-type family and one belonging to the EEP-type family, which shorten the poly(A) tails of mRNA. We will review the present state of structure-function analyses into the CCR4-NOT deadenylases and summarize current understanding of their roles in mRNA degradation. We will also review structural and functional work on the Tob/BTG family of proteins, which are known to interact with the CCR4-NOT complex and which have been reported to suppress deadenylase activity in vitro.

  • Research articles
    Yibing Huang, Jinfeng Huang, Yuxin Chen,
    Protein & Cell, 2010, 1(2): 143-152. https://doi.org/10.1007/s13238-010-0004-3
    Antimicrobial peptides (AMPs), with their extraordinary properties, such as broad-spectrum activity, rapid action and difficult development of resistance, have become promising molecules as new antibiotics. Despite their various mechanisms of action, the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action. Moreover, it is generally accepted that the membrane is the primary target of most AMPs, and the interaction between AMPs and eukaryotic cell membranes (causing toxicity to host cells) limits their clinical application. Therefore, researchers are engaged in reforming or de novo designing AMPs as a ‘single-edged sword’ that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells. To improve the antimicrobial activity of AMPs, the relationship between the structure and function of AMPs has been rigorously pursued. In this review, we focus on the current knowledge of α-helical cationic antimicrobial peptides, one of the most common types of AMPs in nature.
  • Research articles
    Xu Zhang, Bo Huang, Xixi Zhou, Chang Chen,
    Protein & Cell, 2010, 1(7): 675-687. https://doi.org/10.1007/s13238-010-0087-x
    In this study we developed a quantitative proteomic method named ICAT switch by introducing isotope-coded affinity tag (ICAT) reagents into the biotin-switch method, and used it to investigate S-nitrosation in the liver of normal control C57BL/6J mice and type 2 diabetic KK-Ay mice. We got fifty-eight S-nitrosated peptides with quantitative information in our research, among which thirty-seven had changed S-nitrosation levels in diabetic mouse liver. The S-nitrosated peptides belonged to forty-eightproteins(twenty-eightwerenewS-nitrosated proteins), some of which were new targets of S-nitrosation and known to be related with diabetes. S-nitrosation patterns were different between diabetic and normal mice. Gene ontology enrichment results suggested that S-nitrosated proteins are more abundant in amino acid metabolic processes. The network constructed for S-nitrosated proteins by text-mining technology provided clues about the relationship between S-nitrosation and type 2 diabetes. Our work provides a new approach for quantifying S-nitrosated proteins and suggests that the integrative functions of S-nitrosation may take part in pathophysiological processes of type 2 diabetes.
  • RESEARCH ARTICLE
    Ying Jing, Yuesheng Zuo, Yang Yu, Liang Sun, Zhengrong Yu, Shuai Ma, Qian Zhao, Guoqiang Sun, Huifang Hu, Jingyi Li, Daoyuan Huang, Lixiao Liu, Jiaming Li, Zijuan Xin, Haoyan Huang, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Si Wang, Jing Qu, Guang-Hui Liu
    Protein & Cell, 2023, 14(7): 497-512. https://doi.org/10.1093/procel/pwac061

    Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

  • REVIEW
    Zhongfeng Wang, Baojie Li
    Protein & Cell, 2010, 1(12): 1063-1072. https://doi.org/10.1007/s13238-010-0140-9

    Mouse double minute 2 (Mdm2) gene was isolated from a cDNA library derived from transformed mouse 3T3 cells, and was classified as an oncogene as it confers 3T3 and Rat2 cells tumorigenicity when overexpressed. It encodes a nucleocytoplasmic shuttling ubiquitin E3 ligase, with its main target being tumor suppressor p53, which is mutated in more than 50% of human primary tumors. Mdm2’s oncogenic activity is mainly mediated by p53, which is activated by various stresses, especially genotoxic stress, via Atm (ataxia telangiectasia mutated) and Atr (Atm and Rad3-related). Activated p53 inhibits cell proliferation, induces apoptosis or senescence, and maintains genome integrity. Mdm2 is also a target gene of p53 transcription factor. Thus, Mdm2 and p53 form a feedback regulatory loop. External and internal cues, through multiple signaling pathways, can act on Mdm2 to regulate p53 levels and cell proliferation, death, and senescence. This review will focus on how Mdm2 is regulated under genotoxic stress, and by the Akt1-mTOR-S6K1 pathway that is activated by insulin, growth factors, amino acids, or energy status.

  • RESEARCH ARTICLE
    Dmitry Kryndushkin, Reed B. Wickner, Frank Shewmaker
    Protein & Cell, 2011, 2(3): 223-236. https://doi.org/10.1007/s13238-011-1525-0

    Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the premature loss of motor neurons. While the underlying cellular mechanisms of neuron degeneration are unknown, the cytoplasmic aggregation of several proteins is associated with sporadic and familial forms of the disease. Both wild-type and mutant forms of the RNA-binding proteins FUS and TDP-43 accumulate in cytoplasmic inclusions in the neurons of ALS patients. It is not known if these so-called proteinopathies are due to a loss of function or a gain of toxicity resulting from the formation of cytoplasmic aggregates. Here we present a model of FUS toxicity using the yeast Saccharomyces cerevisiae in which toxicity is associated with greater expression and accumulation of FUS in cytoplasmic aggregates. We find that FUS and TDP-43 have a high propensity for co-aggregation, unlike the aggregation patterns of several other aggregation-prone proteins. Moreover, the biophysical properties of FUS aggregates in yeast are distinctly different from many amyloidogenic proteins, suggesting they are not composed of amyloid.

  • REVIEW
    David M. Roy,Logan A. Walsh,Timothy A. Chan
    Protein & Cell, 2014, 5(4): 265-296. https://doi.org/10.1007/s13238-014-0031-6

    Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancerassociated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.

  • RESOURCE
    Weiyun Huang, Minhao Liu, S. Frank Yan, Nieng Yan
    Protein & Cell, 2017, 8(6): 401-438. https://doi.org/10.1007/s13238-017-0372-z

    Voltage-gated sodium (Nav) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Cav) channel Cav1.1 provides a template for homology-based structural modeling of the evolutionarily related Nav channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nav1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nav channels, the analysis presented here serves as the base framework for mechanistic investigation of Nav channelopathies and for potential structure-based drug discovery.

  • REVIEW
    Kyoji Tsuchikama, Zhiqiang An
    Protein & Cell, 2018, 9(1): 33-46. https://doi.org/10.1007/s13238-016-0323-0

    The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. Thisnewantibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/ pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy. Boosted by the successes of FDA-approved Adcetris® and Kadcyla®, this drug class has been rapidly growing along with about 60 ADCs currently in clinical trials. In this article, we briefly review molecular aspects of each component (the antibody, payload, and linker) of ADCs, and then mainly discuss traditional and new technologies of the conjugation and linker chemistries for successful construction of clinically effective ADCs. Current efforts in the conjugation and linker chemistries will provide greater insights into molecular design and strategies for clinically effective ADCs from medicinal chemistry and pharmacology standpoints. The development of site-specific conjugation methodologies for constructing homogeneousADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.

  • RESEARCH ARTICLE
    Zhen Sun, Hua Yu, Jing Zhao, Tianyu Tan, Hongru Pan, Yuqing Zhu, Lang Chen, Cheng Zhang, Li Zhang, Anhua Lei, Yuyan Xu, Xianju Bi, Xin Huang, Bo Gao, Longfei Wang, Cristina Correia, Ming Chen, Qiming Sun, Yu Feng, Li Shen, Hao Wu, Jianlong Wang, Xiaohua Shen, George Q. Daley, Hu Li, Jin Zhang
    Protein & Cell, 2022, 13(7): 490-512. https://doi.org/10.1007/s13238-021-00864-5

    LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28’s role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.

  • LETTER
    Rujin Huang, Jinyang Liu, Xi Chen, Ying Zhi, Shuangyuan Ding, Jia Ming, Yulin Li, Yangming Wang, Jie Na
    Protein & Cell, 2023, 14(2): 153-157. https://doi.org/10.1093/procel/pwac019
  • RESEARCH ARTICLE
    Yu Guo, Jing Wang, Guojun Niu, Wenqing Shui, Yuna Sun, Honggang Zhou, Yaozhou Zhang, Cheng Yang, Zhiyong Lou, Zihe Rao
    Protein & Cell, 2011, 2(5): 384-394. https://doi.org/10.1007/s13238-011-1055-9

    Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are a type of newly discovered antibiotic-resistant bacteria. The rapid pandemic spread of NDM-1 bacteria worldwide (spreading to India, Pakistan, Europe, America, and Chinese Taiwan) in less than 2 months characterizes these microbes as a potentially major global health problem. The drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial populations. The NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics, allowing the bacteria to escape the action of antibiotics. Although the biological functions and structural features of NDM-1 have been proposed according to results from functional and structural investigation of its homologues, the precise molecular characteristics and mechanism of action of NDM-1 have not been clarified. Here, we report the three-dimensional structure of NDM-1 with two catalytic zinc ions in its active site. Biological and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding affinity. The unique features concerning the primary sequence and structural conformation of the active site distinguish NDM-1 from other reported metallo-β-lactamases (MBLs) and implicate its role in wide spectrum drug resistance. We also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 bacteria. Our results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases.

  • REVIEW
    Yuanxi Kang, Jia Guo, Zhiwei Chen
    Protein & Cell, 2013, 4(2): 86-102. https://doi.org/10.1007/s13238-012-2111-9

    The pandemic of human immunodeficiency virus type one (HIV-1), the major etiologic agent of acquired immunodeficiency disease (AIDS), has led to over 33 million people living with the virus, among which 18 million are women and children. Until now, there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts. Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%, an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may take years to achieve. Therefore, there is an urgency of exploring other prophylactic strategies. Recently, antiretroviral treatment as prevention is an exciting area of progress in HIV-1 research. Although effective, the implementation of such strategy faces great financial, political and social challenges in heavily affected regions such as developing countries where drug resistant viruses have already been found with growing incidence. Activating latently infected cells for therapeutic cure is another area of challenge. Since it is greatly difficult to eradicate HIV-1 after the establishment of viral latency, it is necessary to investigate strategies that may close the door to HIV-1. Here, we review studies on non-vaccine strategies in targeting viral entry, which may have critical implications for HIV-1 prevention.

  • RESEARCH ARTICLE
    Priyanka Sathe, Li Wu
    Protein & Cell, 2011, 2(8): 620-630. https://doi.org/10.1007/s13238-011-1088-0

    The pathways leading to the development of different dendritic cell (DC) subsets have long been unclear. In recent years, a number of precursors on the route to DC development, both under steady state and inflammatory conditions, have been described, and the nature of these pathways is becoming clearer. In addition, the development of various knockout mouse models and an in vitro system modelling DC development have revealed the role of numerous cytokines and transcription factors that influence DC development. Here, we review recent findings on the factors important in DC development in the context of the developmental pathways that have been described.

  • Research articles
    Baoli Zhu, Xin Wang, Lanjuan Li,
    Protein & Cell, 2010, 1(8): 718-725. https://doi.org/10.1007/s13238-010-0093-z
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  • COMMENTARY
    Lijuan Sun, Lanjing Ma, Yubo Ma, Faming Zhang, Changhai Zhao, Yongzhan Nie
    Protein & Cell, 2018, 9(5): 397-403. https://doi.org/10.1007/s13238-018-0546-3
  • RESEARCH ARTICLE
    Guoqiang Sun, Yandong Zheng, Xiaolong Fu, Weiqi Zhang, Jie Ren, Shuai Ma, Shuhui Sun, Xiaojuan He, Qiaoran Wang, Zhejun Ji, Fang Cheng, Kaowen Yan, Ziyi Liu, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Renjie Chai, Guang-Hui Liu
    Protein & Cell, 2023, 14(3): 180-201. https://doi.org/10.1093/procel/pwac058

    Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.

  • LETTER
    Fang Yang,Zhikai Li,Jia Hao,Yan Qin
    Protein & Cell, 2014, 5(7): 563-567. https://doi.org/10.1007/s13238-014-0050-3
  • REVIEW
    Haitao Guo, Sheng Shen, Lili Wang, Hongyu Deng
    Protein & Cell, 2010, 1(11): 987-998. https://doi.org/10.1007/s13238-010-0120-0

    Morphogenesis and maturation of viral particles is an essential step of viral replication. An infectious herpesviral particle has a multilayered architecture, and contains a large DNA genome, a capsid shell, a tegument and an envelope spiked with glycoproteins. Unique to herpesviruses, tegument is a structure that occupies the space between the nucleocapsid and the envelope and contains many virus encoded proteins called tegument proteins. Historically the tegument has been described as an amorphous structure, but increasing evidence supports the notion that there is an ordered addition of tegument during virion assembly, which is consistent with the important roles of tegument proteins in the assembly and egress of herpesviral particles. In this review we first give an overview of the herpesvirus assembly and egress process. We then discuss the roles of selected tegument proteins in each step of the process, i.e., primary envelopment, deenvelopment, secondary envelopment and transport of viral particles. We also suggest key issues that should be addressed in the near future.

  • MINI-REVIEW
    Xiao-hong Yao, Yi-fang Ping, Xiu-wu Bian
    Protein & Cell, 2011, 2(4): 266-272. https://doi.org/10.1007/s13238-011-1041-2

    Vasculogenic mimicry (VM), a newly-defined pattern of tumor blood supply, provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis. The biological features of the tumor cells that form VM remain unknown. Cancer stem cells (CSCs) are believed to be tumor-initiating cells, capable of self-renewal and multipotent differentiation, which resemble normal stem cells in phenotype and function. Recently CSCs have been shown to contribute to VM formation as well as angiogenesis. These findings challenge the previous understanding of the cellular basis of VM formation. In this review, we present evidence for participation of CSCs in VM formation. We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche. Based on the importance of VM in tumor progression, it constitutes a novel therapeutic target for cancer.

  • RESEARCH ARTICLE
    Xiang Li, Chuan-Qi Zhong, Rui Wu, Xiaozheng Xu, Zhang-Hua Yang, Shaowei Cai, Xiurong Wu, Xin Chen, Zhiyong Yin, Qingzu He, Dianjie Li, Fei Xu, Yihua Yan, Hong Qi, Changchuan Xie, Jianwei Shuai, Jiahuai Han
    Protein & Cell, 2021, 12(11): 858-876. https://doi.org/10.1007/s13238-020-00810-x

    There remains a significant gap in our quantitative understanding of crosstalk between apoptosis and necroptosis pathways. By employing the SWATH-MS technique, we quantified absolute amounts of up to thousands of proteins in dynamic assembling/deassembling of TNF signaling complexes. Combining SWATH-MS-based network modeling and experimental validation, we found that when RIP1 level is below ∼1000 molecules/cell (mpc), the cell solely undergoes TRADDdependent apoptosis. When RIP1 is above ∼1000 mpc, pro-caspase-8 and RIP3 are recruited to necrosome respectively with linear and nonlinear dependence on RIP1 amount, which well explains the co-occurrence of apoptosis and necroptosis and the paradoxical observations that RIP1 is required for necroptosis but its increase down-regulates necroptosis. Higher amount of RIP1 (>∼46,000 mpc) suppresses apoptosis, leading to necroptosis alone. The relation between RIP1 level and occurrence of necroptosis or total cell death is biphasic. Our study provides a resource for encoding the complexity of TNF signaling and a quantitative picture how distinct dynamic interplay among proteins function as basis sets in signaling complexes, enabling RIP1 to play diverse roles in governing cell fate decisions.

  • REVIEW
    Tao Wen, Guoqing Niu, Tong Chen, Qirong Shen, Jun Yuan, Yong-Xin Liu
    Protein & Cell, 2023, 14(10): 713-725. https://doi.org/10.1093/procel/pwad024

    With the gradual maturity of sequencing technology, many microbiome studies have published, driving the emergence and advance of related analysis tools. R language is the widely used platform for microbiome data analysis for powerful functions. However, tens of thousands of R packages and numerous similar analysis tools have brought major challenges for many researchers to explore microbiome data. How to choose suitable, efficient, convenient, and easy-to-learn tools from the numerous R packages has become a problem for many microbiome researchers. We have organized 324 common R packages for microbiome analysis and classified them according to application categories (diversity, difference, biomarker, correlation and network, functional prediction, and others), which could help researchers quickly find relevant R packages for microbiome analysis. Furthermore, we systematically sorted the integrated R packages (phyloseq, microbiome, MicrobiomeAnalystR, Animalcules, microeco, and amplicon) for microbiome analysis, and summarized the advantages and limitations, which will help researchers choose the appropriate tools. Finally, we thoroughly reviewed the R packages for microbiome analysis, summarized most of the common analysis content in the microbiome, and formed the most suitable pipeline for microbiome analysis. This paper is accompanied by hundreds of examples with 10,000 lines codes in GitHub, which can help beginners to learn, also help analysts compare and test different tools. This paper systematically sorts the application of R in microbiome, providing an important theoretical basis and practical reference for the development of better microbiome tools in the future. All the code is available at GitHub github.com/taowenmicro/EasyMicrobiomeR.

  • LETTER
    Yuxia Wang, Lijie Wu, Tian Wang, Junlin Liu, Fei Li, Longquan Jiang, Zhongbo Fan, Yanan Yu, Na Chen, Qianqian Sun, Qiwen Tan, Tian Hua, Zhi-Jie Liu
    Protein & Cell, 2024, 15(3): 230-234. https://doi.org/10.1093/procel/pwad055
  • RESEARCH ARTICLE
    Chunling Xuan, Yi Shi, Jianxun Qi, Wei Zhang, Haixia Xiao, George F. Gao
    Protein & Cell, 2011, 2(12): 997-1005. https://doi.org/10.1007/s13238-011-1134-y

    There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs. The main component of the current split influenza A virus vaccine is viral hemagglutinin (HA) which induces a strong antibody-mediated immune response. To develop a modern vaccine against influenza A viruses, the current research has been focused on the universal vaccines targeting viral M2, NP and HA proteins. Crystallographic studies have shown that HA forms a trimer embedded on the viral envelope surface, and each monomer consists of a globular head (HA1) and a “rod-like” stalk region (HA2), the latter being more conserved among different HA subtypes and being the primary target for universal vaccines. In this study, we rationally designed the HA head based on the crystal structure of the 2009-pandemic influenza A (H1N1) virus HA as a model, tested its immunogenicity in mice, solved its crystal structure and further examined its immunological characteristics. The results show that the HA globular head can be easily prepared by in vitro refolding in an E. coli expression system, which maintains its intact structure and allows for the stimulation of a strong immune response. Together with recent reports on some similar HA globular head preparations we conclude that structure-based rational design of the HA globular head can be used for subtype-specific vaccines against influenza viruses.

  • COMMUNICATION
    Tao Huang, Chuan Wang, Guoqing Zhang, Lu Xie, Yixue Li
    Protein & Cell, 2012, 3(1): 38-43. https://doi.org/10.1007/s13238-011-1130-2

    Single amino acid polymorphisms (SAPs), also known as non-synonymous single nucleotide polymorphisms (nsSNPs), are responsible for most of human genetic diseases. Discriminate the deleterious SAPs from neutral ones can help identify the disease genes and understand the mechanism of diseases. In this work, a method of deleterious SAP prediction at system level was established. Unlike most existing methods, our method not only considers the sequence and structure information, but also the network information. The integration of network information can improve the performance of deleterious SAP prediction. To make our method available to the public, we developed SySAP (a System-level predictor of deleterious Single Amino acid Polymorphisms), an easy-to-use and high accurate web server. SySAP is freely available at http://www.biosino.org/SySAP/and http://lifecenter.sgst.cn/SySAP/.

  • Research articles
    Qingxin Hua,
    Protein & Cell, 2010, 1(6): 537-551. https://doi.org/10.1007/s13238-010-0069-z
    Insulin is a hormone that is essential for regulating energy storage and glucose metabolism in the body. Insulin in liver, muscle, and fat tissues stimulates the cell to take up glucose from blood and store it as glycogen in liver and muscle. Failure of insulin control causes diabetes mellitus (DM). Insulin is the unique medicine to treat some forms of DM. The population of diabetics has dramatically increased over the past two decades, due to high absorption of carbohydrates (or fats and proteins), lack of physical exercise, and development of new diagnostic techniques. At present, the two largest developing countries (India and China) and the largest developed country (United States) represent the top three countries in terms of diabetic population. Insulin is a small protein, but contains almost all structural features typical of proteins: α-helix, β-sheet, β-turn, high order assembly, allosteric T®R-transition, and conformational changes in amyloidal fibrillation. More than ten years’ efforts on studying insulin disulfide intermediates by NMR have enabled us to decipher the whole picture of insulin folding coupled to disulfide pairing, especially at the initial stage that forms the nascent peptide. Two structural switches are also known to regulate insulin binding to receptors and progress has been made to identify the residues involved in binding. However, resolving the complex structure of insulin and its receptor remains a challenge in insulin research. Nevertheless, the accumulated knowledge of insulin structure has allowed us to specifically design a new ultra-stable and active single-chain insulin analog (SCI-57), and provides a novel way to design super-stable, fast-acting and cheaper insulin formulations for DM patients. Continuing this long journey of insulin study will benefit basic research in proteins and in pharmaceutical therapy.
  • REVIEW
    Xianwei Wang, Zhigang Tian, Hui Peng
    Protein & Cell, 2020, 11(2): 85-96. https://doi.org/10.1007/s13238-019-0647-7

    Innate lymphoid cells (ILCs) are defined as lymphocytes that lack RAG recombinase and do not express diverse antigen receptors; however, recent studies have revealed the adaptive features of ILCs. Mouse cytome-galovirus (MCMV)- and cytokine-induced memory natu-ral killer (NK) cells circulate in the blood and are referred to as conventional memory NK cells. In contrast, virus- and hapten-induced memory NK cells, hapten-induced memory ILC1s, and cytokine-induced memory-like ILC2s exhibit long-term residency in the liver or lung, and are referred to as tissue-resident memory ILCs. Considering their similar migration patterns and mem- ory potential, tissue-resident memory ILCs could be regarded as innate counterparts of resident memory T (TRM) cells. Both tissue-resident memory ILCs and TRM cells share common characteristics in terms of dynam- ics, phenotype, and molecular regulation. The emer-gence of ILC memory expands the basic biology of ILCs and prompts us to re-examine their functions in disease progression. This review discusses the evidence sup-porting tissue-resident memory NK cells and other memory ILC subsets, compares them with TRM cells, and highlights key unsolved questions in this emerging field.

  • CORRECTION
    Xiaoyan Sheng, Chenglei Tian, Linlin Liu, Lingling Wang, Xiaoying Ye, Jie Li, Ming Zeng, Lin Liu
    Protein & Cell, 2020, 11(7): 540-541. https://doi.org/10.1007/s13238-019-00675-9
  • CORRECTION
    Le Wen, Fei Zhao, Yong Qiu, Shuang Cheng, Jin-Yan Sun, Wei Fang, Simon Rayner, Michael A. McVoy, Xing-Jun Jiang, Qiyi Tang, Fang-Cheng Li, Fei Hu, Min-Hua Luo
    Protein & Cell, 2021, 12(4): 313. https://doi.org/10.1007/s13238-020-00787-7
  • RESEARCH ARTICLE
    Furong Gui, Tianming Lan, Yue Zhao, Wei Guo, Yang Dong, Dongming Fang, Huan Liu, Haimeng Li, Hongli Wang, Ruoshi Hao, Xiaofang Cheng, Yahong Li, Pengcheng Yang, Sunil Kumar Sahu, Yaping Chen, Le Cheng, Shuqi He, Ping Liu, Guangyi Fan, Haorong Lu, Guohai Hu, Wei Dong, Bin Chen, Yuan Jiang, Yongwei Zhang, Hanhong Xu, Fei Lin, Bernard Slipper, Alisa Postma, Matthew Jackson, Birhan Addisie Abate, Kassahun Tesfaye, Aschalew Lemma Demie, Meseret Destaw Bayeleygne, Dawit Tesfaye Degefu, Feng Chen, Paul K. Kuria, Zachary M. Kinyua, Tong-Xian Liu, Huanming Yang, Fangneng Huang, Xin Liu, Jun Sheng, Le Kang
    Protein & Cell, 2022, 13(7): 513-531. https://doi.org/10.1007/s13238-020-00795-7

    The fall armyworm (FAW), Spodoptera frugiperda, is a destructive pest native to America and has recently become an invasive insect pest in China. Because of its rapid spread and great risks in China, understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies. Here, we assembled a chromosome-level genome of a male FAW (SFynMstLFR) and compared resequencing results of the populations from America, Africa, and China. Strain identification of 163 individuals collected from America, Africa and China showed that both C and R strains were found in the American populations, while only C strain was found in the Chinese and African populations. Moreover, population genomics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations. Taken together, FAWs invaded into China were most likely originated from Africa. Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW, of which 283 genes are specific to FAW. Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles, and several detoxification genes such as AOX, UGT and GST specially responded to the pesticides. These findings will be useful in developing effective strategies for management of FAW in China and other invaded areas.

  • REVIEW
    Xuelian Luo
    Protein & Cell, 2010, 1(9): 811-819. https://doi.org/10.1007/s13238-010-0105-z

    The Hippo pathway plays key roles in animal development. It suppresses tumorigenesis by controlling the transcription of the target genes that are critical for cell proliferation and apoptosis. The transcriptional coactivator YAP is the major downstream effector of the Hippo signaling. Upon extracellular stimulation, a kinase cascade in the Hippo pathway phosphorylates YAP and promotes its cytoplasmic sequestration by 14-3-3 and ubiquitin-dependent degradation. When the Hippo pathway is turned off, YAP (which lacks a DNA-binding domain) is dephosphorylated and translocates to the nucleus, where it associates with the transcription factor TEAD to form a functional heterodimeric transcription factor and to promote the expression of the Hippo-responsive genes. Recently, structures of the YAP-binding domain of TEAD alone or in complex with YAP have revealed the atomic details of the TEAD-YAP interaction. Here, I review these exciting advances, propose a strategy for targeting the TEAD-YAP interaction using small molecules, and suggest potential mechanisms by which phosphorylation and 14-3-3 binding regulate the cytoplasmic retention of YAP.

  • RESEARCH ARTICLE
    Xiaolei Liu, Biyan Duan, Zhaokang Cheng, Xiaohua Jia, Lina Mao, Hao Fu, Yongzhe Che, Lailiang Ou, Lin Liu, Deling Kong
    Protein & Cell, 2011, 2(10): 845-854. https://doi.org/10.1007/s13238-011-1097-z

    Bone marrow mesenchymal stem cells (MSCs) are considered as a promising cell source to treat the acute myocardial infarction. However, over 90% of the stem cells usually die in the first three days of transplantation. Survival potential, migration ability and paracrine capacity have been considered as the most important three factors for cell transplantation in the ischemic cardiac treatment. We hypothesized that stromal-derived factor-1 (SDF-1)/CXCR4 axis plays a critical role in the regulation of these processes. In this study, apoptosis was induced by exposure of MSCs to H2O2 for 2 h. After re-oxygenation, the SDF-1 pretreated MSCs demonstrated a significant increase in survival and proliferation. SDF-1 pretreatment also enhanced the migration and increased the secretion of pro-survival and angiogenic cytokines including basic fibroblast growth factor and vascular endothelial growth factor. Western blot and RT-PCR demonstrated that SDF-1 pretreatment significantly activated the pro-survival Akt and Erk signaling pathways and up-regulated Bcl-2/Bax ratio. These protective effects were partially inhibited by AMD3100, an antagonist of CXCR4. We conclude that the SDF-1/CXCR4 axis is critical for MSC survival, migration and cytokine secretion.

  • MINI-REVIEW
    Ting Ting Sun, Chin Man Chung, Hsiao Chang Chan
    Protein & Cell, 2011, 2(2): 92-98. https://doi.org/10.1007/s13238-011-1022-5

    Fertilization is a process involving multiple steps that lead to the final fusion of one sperm and the oocyte to form the zygote. One of the steps, acrosome reaction (AR), is an exocytosis process, during which the outer acrosome membrane fuses with the inner sperm membrane, leading to the release of acrosome enzymes that facilitate sperm penetration of the egg investments. Though AR has been investigated for decades, the initial steps of AR in vivo, however, remain largely unknown. A well elucidated model holds the view that AR occurs on the surface of the zona pellucida (ZP), which is triggered by binding of sperm with one of the ZP glycosylated protein, ZP3. However, this model fails to explain the large number of ‘falsely’ acrosome-reacted sperms found within the cumulus layer in many species examined. With the emerging evidence of cross-talk between sperm and cumulus cells, the potential significance of AR in the cumulus oophorus, the outer layer of the egg, has been gradually revealed. Here we review the acrosome status within the cumulus layer, the cross-talk between sperm and cumulus cells with the involvement of a novel sperm-released factor, NYD-SP8, and re-evaluate the importance and physiological significance of the AR in the cumulus in fertilization.

  • REVIEW
    Ming Liu,Lingxi Jiang,Xin-Yuan Guan
    Protein & Cell, 2014, 5(9): 673-691. https://doi.org/10.1007/s13238-014-0065-9

    Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-apoptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and lncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.

  • REVIEW
    Junsheng Yang, Zhuangzhuang Zhao, Mingxue Gu, Xinghua Feng, Haoxing Xu
    Protein & Cell, 2019, 10(1): 8-19. https://doi.org/10.1007/s13238-018-0523-x

    Cells utilize calcium ions (Ca2+) to signal almost all aspects of cellular life, ranging from cell proliferation to cell death, in a spatially and temporally regulated manner. A key aspect of this regulation is the compartmentalization of Ca2+ in various cytoplasmic organelles that act as intracellular Ca2+ stores. Whereas Ca2+ release from the large-volume Ca2+ stores, such as the endoplasmic reticulum (ER) and Golgi apparatus, are preferred for signal transduction, Ca2+ release from the small-volume individual vesicular stores that are dispersed throughout the cell, such as lysosomes, may be more useful in local regulation, such as membrane fusion and individualized vesicular movements. Conceivably, these two types of Ca2+ stores may be established, maintained or refilled via distinct mechanisms. ER stores are refilled through sustained Ca2+ influx at ER-plasma membrane (PM) membrane contact sites (MCSs). In this review, we discuss the release and refilling mechanisms of intracellular small vesicular Ca2+ stores, with a special focus on lysosomes. Recent imaging studies of Ca2+ release and organelle MCSs suggest that Ca2+ exchange may occur between two types of stores, such that the small stores acquire Ca2+ from the large stores via ER-vesicle MCSs. Hence vesicular stores like lysosomes may be viewed as secondary Ca2+ stores in the cell.

  • RESEARCH ARTICLE
    Fang Wang, Weiqi Zhang, Qiaoyan Yang, Yu Kang, Yanling Fan, Jingkuan Wei, Zunpeng Liu, Shaoxing Dai, Hao Li, Zifan Li, Lizhu Xu, Chu Chu, Jing Qu, Chenyang Si, Weizhi Ji, Guang-Hui Liu, Chengzu Long, Yuyu Niu
    Protein & Cell, 2020, 11(11): 809-824. https://doi.org/10.1007/s13238-020-00740-8

    Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.

  • REVIEW
    Xiya Zhang, Tao Li, Jianping Ou, Junjiu Huang, Puping Liang
    Protein & Cell, 2022, 13(5): 316-335. https://doi.org/10.1007/s13238-021-00838-7

    Recent advances in genome editing, especially CRISPRCas nucleases, have revolutionized both laboratory research and clinical therapeutics. CRISPR-Cas nucleases, together with the DNA damage repair pathway in cells, enable both genetic diversification by classical non-homologous end joining (c-NHEJ) and precise genome modification by homology-based repair (HBR). Genome editing in zygotes is a convenient way to edit the germline, paving the way for animal disease model generation, as well as human embryo genome editing therapy for some life-threatening and incurable diseases. HBR efficiency is highly dependent on the DNA donor that is utilized as a repair template. Here, we review recent progress in improving CRISPR-Cas nuclease-induced HBR in mammalian embryos by designing a suitable DNA donor. Moreover, we want to provide a guide for producing animal disease models and correcting genetic mutations through CRISPR-Cas nuclease-induced HBR in mammalian embryos. Finally, we discuss recent developments in precise genomemodification technology based on the CRISPR-Cas system.