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  • RESEARCH ARTICLE
    Kai Jiang, Yue Xu, Dandan Wang, Feng Chen, Zizhuo Tu, Jie Qian, Sheng Xu, Yixiang Xu, John Hwa, Jian Li, Hongcai Shang, Yaozu Xiang
    Protein & Cell, 2022, 13(5): 336-359. https://doi.org/10.1007/s13238-020-00809-4

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na+/H+ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA’s cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.

  • LETTER
    Mengyue Lv, Dan Cao, Liwen Zhang, Chi Hu, Shukai Li, Panrui Zhang, Lianbang Zhu, Xiao Yi, Chaoliang Li, Alin Yang, Zhentao Yang, Yi Zhu, Kaiguang Zhang, Wen Pan
    Protein & Cell, 2021, 12(12): 965-970. https://doi.org/10.1007/s13238-021-00857-4
  • RESEARCH ARTICLE
    Weili Yang, Xiangyu Guo, Zhuchi Tu, Xiusheng Chen, Rui Han, Yanting Liu, Sen Yan, Qi Wang, Zhifu Wang, Xianxian Zhao, Yunpeng Zhang, Xin Xiong, Huiming Yang, Peng Yin, Huida Wan, Xingxing Chen, Jifeng Guo, Xiao-Xin Yan, Lujian Liao, Shihua Li, Xiao-Jiang Li
    Protein & Cell, 2022, 13(1): 26-46. https://doi.org/10.1007/s13238-021-00888-x

    In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

  • COMMENTARY
    Chao Mao, Guang Lei, Li Zhuang, Boyi Gan
    Protein & Cell, 2022, 13(5): 313-315. https://doi.org/10.1007/s13238-021-00892-1
  • RECOLLECTION
    Yejing Ge
    Protein & Cell, 2022, 13(5): 309-312. https://doi.org/10.1007/s13238-021-00829-8
  • RESEARCH ARTICLE
    Shi Wei, Miaomiao Dai, Chi Zhang, Kai Teng, Fengwei Wang, Hongbo Li, Weipeng Sun, Zihao Feng, Tiebang Kang, Xinyuan Guan, Ruihua Xu, Muyan Cai, Dan Xie
    Protein & Cell, 2021, 12(10): 788-809. https://doi.org/10.1007/s13238-020-00766-y

    Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.

  • RECOLLECTION
    Shiying Li, Wei Chen, Shengjun Wen
    Protein & Cell, 2021, 12(11): 825-831. https://doi.org/10.1007/s13238-020-00798-4
  • REVIEW
    Guang Lei, Chao Mao, Yuelong Yan, Li Zhuang, Boyi Gan
    Protein & Cell, 2021, 12(11): 836-857. https://doi.org/10.1007/s13238-021-00841-y

    Ferroptosis, an iron-dependent form of regulated cell death driven by peroxidative damages of polyunsaturated-fatty-acid-containing phospholipids in cellular membranes, has recently been revealed to play an important role in radiotherapy-induced cell death and tumor suppression, and to mediate the synergy between radiotherapy and immunotherapy. In this review, we summarize known as well as putative mechanisms underlying the crosstalk between radiotherapy and ferroptosis, discuss the interactions between ferroptosis and other forms of regulated cell death induced by radiotherapy, and explore combination therapeutic strategies targeting ferroptosis in radiotherapy and immunotherapy. This review will provide important frameworks for future investigations of ferroptosis in cancer therapy.

  • RESEARCH ARTICLE
    Wan Zhao, Junjie Zhu, Hong Lu, Jiaming Zhu, Fei Jiang, Wei Wang, Lan Luo, Le Kang, Feng Cui
    Protein & Cell, 2022, 13(5): 360-378. https://doi.org/10.1007/s13238-021-00822-1

    Rice stripe virus (RSV) transmitted by the small brown planthopper causes severe rice yield losses in Asian countries. Although viral nuclear entry promotes viral replication in host cells, whether this phenomenon occurs in vector cells remains unknown. Therefore, in this study, we systematically evaluated the presence and roles of RSV in the nuclei of vector insect cells. We observed that the nucleocapsid protein (NP) and viral genomic RNAs were partially transported into vector cell nuclei by utilizing the importin α nuclear transport system. When blocking NP nuclear localization, cytoplasmic RSV accumulation significantly increased. In the vector cell nuclei, NP bound the transcription factor YY1 and affected its positive regulation to FAIM. Subsequently, decreased FAIM expression triggered an antiviral caspase-dependent apoptotic reaction. Our results reveal that viral nuclear entry induces completely different immune effects in vector and host cells, providing new insights into the balance between viral load and the immunity pressure in vector insects.

  • LETTERS
    Yu-Sheng Chen, Shuaiyao Lu, Bing Zhang, Tingfu Du, Wen-Jie Li, Meng Lei, Yanan Zhou, Yong Zhang, Penghui Liu, Yong-Qiao Sun, Yong-Liang Zhao, Ying Yang, Xiaozhong Peng, Yun-Gui Yang
    Protein & Cell, 2022, 13(5): 379-385. https://doi.org/10.1007/s13238-021-00861-8
  • RECOLLECTION
    Zheng Tan, Jun Tang, Feng Wang, Xiaocui Li, Yanlian Chen, Zhou Songyang
    Protein & Cell, 2022, 13(1): 1-3. https://doi.org/10.1007/s13238-021-00875-2
  • COMMENTARY
    Hang-Yu Zhou, Cheng-Yang Ji, Hang Fan, Na Han, Xiao-Feng Li, Aiping Wu, Cheng-Feng Qin
    Protein & Cell, 2021, 12(11): 832-835. https://doi.org/10.1007/s13238-021-00847-6
  • RECOLLECTION
    Xunfeng Xu, Lei Fu
    Protein & Cell, 2021, 12(12): 903-905. https://doi.org/10.1007/s13238-020-00758-y
  • RECOLLECTION
    Xin Zhang, Huan Liu
    Protein & Cell, 2022, 13(2): 79-81. https://doi.org/10.1007/s13238-021-00870-7
  • LETTER
    Si Wang, Yuxuan Zheng, Qingqing Li, Xiaojuan He, Ruotong Ren, Weiqi Zhang, Moshi Song, Huifang Hu, Feifei Liu, Guoqiang Sun, Shuhui Sun, Zunpeng Liu, Yang Yu, Piu Chan, Guo-Guang Zhao, Qi Zhou, Guang-Hui Liu, Fuchou Tang, Jing Qu
    Protein & Cell, 2021, 12(11): 889-898. https://doi.org/10.1007/s13238-020-00791-x
  • RECOLLECTION
    Yong Wang, Wei Chen, Shiying Li, Bin Yin
    Protein & Cell, 2022, 13(10): 701-706. https://doi.org/10.1007/s13238-021-00849-4
  • REVIEW
    Hui Yang, Bruce Beutler, Duanwu Zhang
    Protein & Cell, 2022, 13(8): 559-579. https://doi.org/10.1007/s13238-021-00856-5

    Precursor messenger RNA (pre-mRNA) splicing is catalyzed by an intricate ribonucleoprotein complex called the spliceosome. Although the spliceosome is considered to be general cell “housekeeping” machinery, mutations in core components of the spliceosome frequently correlate with cellor tissue-specific phenotypes and diseases. In this review, we expound the links between spliceosome mutations, aberrant splicing, and human cancers. Remarkably, spliceosome-targeted therapies (STTs) have become efficient anti-cancer strategies for cancer patients with splicing defects. We also highlight the links between spliceosome and immune signaling. Recent studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to missplicing of immune-related genes. Furthermore, several core spliceosome components harbor splicing-independent immune functions within the cell, expanding the functional repertoire of these diverse proteins.

  • RECOLLECTION
    Wei Gong, Yijing Shen, Jiaqi Bao, Yike Ying, Han Zhou, Zhifeng Wu
    Protein & Cell, 2021, 12(10): 747-750. https://doi.org/10.1007/s13238-019-00663-z
  • 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.

  • RESEARCH ARTICLE
    He Li, Lei Zhu, Rong Wang, Lihui Xie, Jie Ren, Shuai Ma, Weiqi Zhang, Xiuxing Liu, Zhaohao Huang, Binyao Chen, Zhaohuai Li, Huyi Feng, Guang-Hui Liu, Si Wang, Jing Qu, Wenru Su
    Protein & Cell, 0: 422-445. https://doi.org/10.1007/s13238-021-00882-3

    Aging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure. Lymph nodes, which filter the lymph to identify and fight infections, play a central role in this process. However, careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking. We combined single-cell RNA sequencing (scRNA-seq) with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes (CDLNs) of both young and old mice with or without experimental autoimmune uveitis (EAU). We found extensive and complicated changes in the cellular constituents of CDLNs during aging. When confronted with autoimmune challenges, old mice developed milder EAU compared to young mice. Within this EAU process, we highlighted that the pathogenicity of T helper 17 cells (Th17) was dampened, as shown by reduced GM-CSF secretion in old mice. The mitigated secretion of GM-CSF contributed to alleviation of IL-23 secretion by antigen-presenting cells (APCs) and may, in turn, weaken APCs’ effects on facilitating the pathogenicity of Th17 cells. Meanwhile, our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs. Overall, aging altered immune cell responses, especially through toning down Th17 cells, counteracting EAU challenge in old mice.

  • COMMENTARY
    Bing Liu, Daniela Duenas, Li Zheng, Karen Reckamp, Binghui Shen
    Protein & Cell, 2022, 13(2): 82-89. https://doi.org/10.1007/s13238-021-00855-6
  • RESEARCH ARTICLE
    Yao Zhao, Xiaoyu Du, Yinkai Duan, Xiaoyan Pan, Yifang Sun, Tian You, Lin Han, Zhenming Jin, Weijuan Shang, Jing Yu, Hangtian Guo, Qianying Liu, Yan Wu, Chao Peng, Jun Wang, Chenghao Zhu, Xiuna Yang, Kailin Yang, Ying Lei, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Lei Sun, Leike Zhang, Zihe Rao, Haitao Yang
    Protein & Cell, 2021, 12(11): 877-888. https://doi.org/10.1007/s13238-021-00836-9

    A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARSCoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three “hot” spots on PLpro, including the substratebinding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

  • LETTER
    Xiangfeng Kong, Zikang Wang, Renxia Zhang, Xing Wang, Yingsi Zhou, Linyu Shi, Hui Yang
    Protein & Cell, 2021, 12(11): 899-902. https://doi.org/10.1007/s13238-021-00862-7
  • RECOLLECTION
    Wei Xie, Ben-Yu Guo, Yanyan Qian
    Protein & Cell, 2022, 13(6): 387-393. https://doi.org/10.1007/s13238-021-00850-x
  • LETTER
    Ni Zong, Min Wang, Yinghui Fu, Dan Shen, Yong-Chun Yu
    Protein & Cell, 2022, 13(2): 141-147. https://doi.org/10.1007/s13238-021-00851-w
  • LETTER
    Bin Li, Yongkun Zhan, Qianqian Liang, Chen Xu, Xinyan Zhou, Huanhuan Cai, Yufan Zheng, Yifan Guo, Lei Wang, Wenqing Qiu, Baiping Cui, Chao Lu, Ruizhe Qian, Ping Zhou, Haiyan Chen, Yun Liu, Sifeng Chen, Xiaobo Li, Ning Sun
    Protein & Cell, 2022, 13(1): 65-71. https://doi.org/10.1007/s13238-021-00843-w
  • REVIEW
    Xiaofei Zhang, Zhuo Ma, Eli Song, Tao Xu
    Protein & Cell, 2022, 13(4): 239-257. https://doi.org/10.1007/s13238-021-00831-0

    Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved in the development, structure, and function of human pancreatic islets under pathological conditions. Stem cell-based islet organoids faithfully recapitulate islet development invitroand provide large amounts of three-dimensional functional islet biomimetic materials with a morphological structure and cellular composition similar to those of native islets. Thus, islet organoids hold great promise for modeling islet development and function, deciphering the mechanisms underlying the onset of diabetes, providing an invitrohuman organ model for infection of viruses such as SARS-CoV-2, and contributing to drug screening and autologous islet transplantation. However, the currently established islet organoids are generally immature compared with native islets, and further efforts should be made to improve the heterogeneity and functionality of islet organoids, making it an authentic and informative disease model for diabetes. Here, we review the advances and challenges in the generation of islet organoids, focusing on human pluripotent stem cell-derived islet organoids, and the potential applications of islet organoids as disease models and regenerative therapies for diabetes.

  • PREVIEW
    Zhiyu Sun, Jiangyu Ye, Junying Yuan
    Protein & Cell, 2022, 13(1): 4-5. https://doi.org/10.1007/s13238-021-00889-w
  • REVIEW
    Juli Bai, Feng Liu
    Protein & Cell, 2022, 13(2): 90-101. https://doi.org/10.1007/s13238-021-00869-0

    The cyclic GMP-AMP (cGAMP) synthase (cGAS) has been identified as a cytosolic double stranded DNA sensor that plays a pivotal role in the type I interferon and inflammation responses via the STING-dependent signaling pathway. In the past several years, a growing body of evidence has revealed that cGAS is also localized in the nucleus where it is associated with distinct nuclear substructures such as nucleosomes, DNA replication forks, the double-stranded breaks, and centromeres, suggesting that cGAS may have other functions in addition to its role in DNA sensing. However, while the innate immune function of cGAS is well established, the non-canonical nuclear function of cGAS remains poorly understood. Here, we review our current understanding of the complex nature of nuclear cGAS and point to open questions on the novel roles and the mechanisms of action of this protein as a key regulator of cell nuclear function, beyond its well-established role in dsDNA sensing and innate immune response.

  • 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.