近日，中国农业科学院哈尔滨兽医研究所基础免疫团队郑永辉研究员和张险峰博士在艾滋病天然免疫研究领域获得新发现，揭示出艾滋病病毒一个“软肋”的机制，有望为开发新的治疗方法提供新的靶向依据。相关研究成果以“Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction”为题在线发表在国际病毒学著名专业期刊《Journal of Virology）》。
丝氨酸整合因子（SERINC）是一种膜蛋白，其家族共有5个成员，其中SERINC5和SERINC3是目前最新发现的抗艾滋病病毒的天然免疫分子，可阻断病毒感染新的细胞，从而降低病毒的感染力。然而，对于SERINC家族各成员的抗病毒活性、体内表达以及抗病毒机理，科研人员还知之甚少。
Analysis of Ser family anti-HIV-1 activities
张险峰博士通过对SERINC家族5个成员系统性比对，不仅发现SERINC5具有最高的抗病毒活性，还检测到了该分子在人体细胞中表达的5种不同分子亚型。进一步研究发现，5种亚型中只有I亚型能够高效表达，相对于其它亚型，I亚型多了一个跨膜区，从而增强了蛋白稳定性并产生抗病毒效力。同时，I亚型在外周血单核细胞和巨噬细胞中表达丰富，预示其在抵抗病毒感染中的具有重要功能。
郑永辉研究员近年来致力于针对病毒囊膜糖蛋白的宿主天然免疫分子机制的研究。他表示说，这一最新结果揭示了艾滋病病毒一个“软肋”，为开发新的治疗方法提供了新策略。
ABSTRACTAmong the five serine incorporator (SERINC) family members, SERINC5 (Ser5) was reported to strongly inhibit HIV-1 replication, which is counteracted by Nef. Ser5produces 5 alternatively spliced isoforms: Ser5-001 has 10 putative transmembrane domains, whereas Ser5-004, -005, -008a, and -008b do not have the last one. Here, we confirmed the strong Ser5 anti-HIV-1 activity and investigated its isoforms' expression and antiviral activity. It was found thatSer5-001 transcripts were detected at least 10-fold more than the other isoforms by real-time quantitative PCR. When Ser5-001 and its two isoforms Ser5-005, and Ser5-008a were expressed from the same mammalian expression vector, only Ser5-001 was stably expressed, whereas the others were poorly expressed due to rapid degradation. In addition, unlike the other isoforms that are located mainly in the cytoplasm, Ser5-001 is localized primarily to the plasma membrane. To map the critical determinant, Ser5 mutants bearing C-terminal deletions were created. It was found that the 10th transmembrane domain is required for Ser5 stable expression and plasma membrane localization. As expected, only Ser5-001 strongly inhibits HIV-1 infectivity, whereas the other Ser5 isoforms and mutants that do not have the 10th transmembrane show a very poor activity. It was also observed that the Nef counteractive activity could be easily saturated by Ser5 overexpression. Thus, we conclude that Ser5-001 is the predominant antiviral isoform that restricts HIV-1, and the 10th transmembrane domain plays a critical role in this process by regulating its protein stability and plasma membrane targeting.
IMPORTANCE HIV and SIV express a small protein Nef to enhance viral pathogenesis in vivo. Nef has an important in vitro function, which is to make virus particles more infectious, but the mechanism has been unclear. Recently, Nef was reported to counteract a novel anti-HIV host protein SERINC5 (Ser5). Ser5 has five alternatively spliced isoforms including Ser5-001, 004, 005, 008a, and 008b, and only Ser5-001 has an extra C-terminal transmembrane domain. We now show that the Ser5-001 transcripts are produced at least 10-fold more than the others, and only Ser5-001 produces stable proteins that are targeted to plasma membrane. Importantly, only Ser5-001 shows a strong anti-HIV-1 activity. We further demonstrate that the extra transmembrane domain is required for Ser5 stable expression and plasma membrane localization. These results suggest that plasma membrane localization is required for Ser5 antiviral activity, and Ser5-001 is the predominant isoform that contributes to the activity.
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郑永辉 研究员 中国农业科学院哈尔滨兽医研究所基础免疫团队首席科学家 博士，研究员，博士研究生导师，1964年8月生于哈尔滨。1993年获得日本文部省国费奖学金资助，1998获得日本医学科学博士学位。1998年开始到美国做博士后研究，先后在美国范德堡大学和旧金山加利福尼亚大学从事博士后研究。2005年起在美国密西根州立大学微生物和分子遗传系任预备终身教职并组建自己的天然免疫研究团队,在该领域取得重要进展，于2011年获得终身职位,成为该系终身副教授。2013年受聘于中国农业科学院哈尔滨兽医研究所基础免疫学创新团队首席科学家。多年来承担了R01,R56,K02等多项美国NIH的重大研究专项，为多个国际知名期刊的审稿人，已在Nature Cell Biology、PNAS等多个国际知名学术期刊发表研究论文35篇，总影响因子超过200。 |
来源：中国农业科学院哈尔滨兽医研究所，编辑：rojjer
发表于 2017-4-25 10:00:01
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