Aug 2017, Volume 8 Issue 8

Cover illustration

  • Entero virus 71 (EV71) is a most common causative agent of hand, foot, and mouth disease (HFMD). SCARB2 is the main receptor for EV71 and critical for both viral infection and pathogenesis. In this issue, Zhang and colleagues generated a monoclonal antibody JL2, which binds human but not mouse SCARB2 and blocks EV71 infection effectively. Structural views of SCARB2-JL2 complex reveal that JL2 binds to the apical region of SCARB2 involving α-helices 2, 5, and 14. Three regions [Detail] ...

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    Jianping Xu
    Haoyi Wang
    Yunyun Luo, Dovile Sinkeviciute, Yi He, Morten Karsdal, Yves Henrotin, Ali Mobasheri, Patrik Önnerfjord, Anne Bay-Jensen

    Articular cartilage is a connective tissue consisting of a specialized extracellular matrix (ECM) that dominates the bulk of its wet and dry weight. Type II collagen and aggrecan are the main ECM proteins in cartilage. However, little attention has been paid to less abundant molecular components, especially minor collagens, including type IV, VI, IX, X, XI, XII, XIII, and XIV, etc. Although accounting for only a small fraction of the mature matrix, these minor collagens not only play essential structural roles in the mechanical properties, organization, and shape of articular cartilage, but also fulfil specific biological functions. Genetic studies of these minor collagens have revealed that they are associated with multiple connective tissue diseases, especially degenerative joint disease. The progressive destruction of cartilage involves the degradation of matrix constituents including these minor collagens. The generation and release of fragmented molecules could generate novel biochemical markers with the capacity to monitor disease progression, facilitate drug development and add to the existing toolbox for in vitro studies, preclinical research and clinical trials.

    Hua Li, Yangbing Zhao

    Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment that has recently been undergoing rapid development. However, there are still some major challenges, including precise tumor targeting to avoid off-target or “on-target/off-tumor” toxicity, adequate T cell infiltration and migration to solid tumors and T cell proliferation and persistence across the physical and biochemical barriers of solid tumors. In this review, we focus on the primary challenges and strategies to design safe and effective CAR T cells, including using novel cutting-edge technologies for CAR and vector designs to increase both the safety and efficacy, further T cell modification to overcome the tumorassociated immune suppression, and using gene editing technologies to generate universal CAR T cells. All these efforts promote the development and evolution of CAR T cell therapy and move toward our ultimate goal—curing cancer with high safety, high efficacy, and low cost.

    Xuyuan Zhang, Pan Yang, Nan Wang, Jialong Zhang, Jingyun Li, Hao Guo, Xiangyun Yin, Zihe Rao, Xiangxi Wang, Liguo Zhang

    Entero virus 71 (EV71) causes hand, foot, and mouth disease (HFMD) and occasionally leads to severe neurological complications and even death. Scavenger receptor class B member 2 (SCARB2) is a functional receptor for EV71, that mediates viral attachment, internalization, and uncoating. However, the exact binding site of EV71 on SCARB2 is unknown. In this study, we generated a monoclonal antibody (mAb) that binds to human but not mouse SCARB2. It is named JL2, and it can effectively inhibit EV71 infection of target cells. Using a set of chimeras of human and mouse SCARB2, we identified that the region containing residues 77–113 of human SCARB2 contributes significantly to JL2 binding. The structure of the SCARB2-JL2 complex revealed that JL2 binds to the apical region of SCARB2 involving α-helices 2, 5, and 14. Our results provide new insights into the potential binding sites for EV71 on SCARB2 and the molecular mechanism of EV71 entry.

    Puping Liang, Hongwei Sun, Ying Sun, Xiya Zhang, Xiaowei Xie, Jinran Zhang, Zhen Zhang, Yuxi Chen, Chenhui Ding, Yuanyan Xiong, Wenbin Ma, Dan Liu, Junjiu Huang, Zhou Songyang

    Targeted point mutagenesis through homologous recombination has been widely used in genetic studies and holds considerable promise for repairing diseasecausing mutations in patients. However, problems such as mosaicism and low mutagenesis efficiency continue to pose challenges to clinical application of such approaches. Recently, a base editor (BE) system built on cytidine (C) deaminase and CRISPR/Cas9 technology was developed as an alternative method for targeted point mutagenesis in plant, yeast, and human cells. Base editors convert C in the deamination window to thymidine (T) efficiently, however, it remains unclear whether targeted base editing in mouse embryos is feasible. In this report, we generated a modified highfidelity version of base editor 2 (HF2-BE2), and investigated its base editing efficacy in mouse embryos. We found that HF2-BE2 could convert C to T efficiently, with up to 100% biallelic mutation efficiency in mouse embryos. Unlike BE3, HF2-BE2 could convert C to T on both the target and non-target strand, expanding the editing scope of base editors. Surprisingly, we found HF2-BE2 could also deaminate C that was proximal to the gRNA-binding region. Taken together, our work demonstrates the feasibility of generating point mutations in mouse by base editing, and underscores the need to carefully optimize base editing systems in order to eliminate proximal-site deamination.

    Shulin Mou, Xiaoxiao Zhang, Zhifu Han, Jiawei Wang, Xinqi Gong, Jijie Chai
    Li-Dan Hu, Xiang-Jun Chen, Xiao-Yan Liao, Yong-Bin Yan
    Min Liu, Xuejun C. Zhang