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The role of SERINC5 in HIV-1 replication

SERINC5 在 HIV-1 复制中的作用

基本信息

批准号：
9974474
负责人：
YONG-HUI ZHENG
金额：
$ 39.13万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974474
关键词：
Adaptor Signaling Protein Affect Alternative Splicing Anabolism Anti-Retroviral Agents Antiviral Agents Binding Binding Proteins Biological Assay Cell membrane Cells Complement Complex Cyclin-Dependent Kinases Degradation Pathway Destinations Development Down-Regulation Drug Targeting Endocytosis Endosomes Equine Infectious Anemia Virus Exhibits Family Fluorescence Gene Expression Genome Stability Goals HIV Envelope Protein gp120 HIV-1 Homo Human Infection Integral Membrane Protein Investigation K-cyclin Laboratories Lead Lysosomes Mediating Membrane Fusion Molecular Molecular Conformation Murine leukemia virus Outcome Pathway interactions Pharmacology Phosphatidylserines Phosphorylation Play Prevalence Primate Lentiviruses Protein Isoforms Proteins Public Health Recycling Reporting Research Resistance Retroviridae Role Sequence Homology Serine Sphingolipids Testing Translating Transmembrane Domain Ubiquitination Viral Viral Proteins Virion Virus Virus Replication Yeasts antiretroviral therapy base dimer env Gene Products env Glycoproteins late endosome member neutralizing antibody novel novel strategies receptor receptor binding receptor mediated endocytosis recruit screening trafficking viral rescue virology yeast two hybrid system

项目摘要

SERINC5 (Ser5) is a novel restriction factor that strongly blocks HIV-1 entry. Ser5 belongs to the serine incorporator (SERINC) family that has five members (1 to 5). They are type III integral membrane proteins with 9-11 transmembrane domains. Ser5 and Ser3 were initially identified as the counteractive target of HIV-1 Nef that increases viral infectivity. Although SERINC proteins share 31-58% sequence homology, only Ser5 and Ser3 have antiviral activities, albeit the Ser3 activity is weak. In addition, although the Ser4 antiviral activity was reported, it is poorly expressed at protein levels. Ser5 is antagonized by HIV-1 Nef as well as MLV glycoGag and EIAV S2. The Nef antagonism of Ser5 plays an important role in the prevalence of primate lentiviruses in their hosts. Thus, Ser5 is an important restriction factor for retroviruses. Our goal is to investigate the molecular mechanisms of how Ser5 inhibits HIV-1 replication and conversely, how Ser5 is counteracted by Nef. First, we will elucidate how Ser5 blocks HIV-1 entry. Ser5 is packaged into virions to block viral entry, but the mechanism is still unclear. It is also unclear why the Ser5 inhibition depends on viral Env glycoproteins. Tier 1 viruses, which are largely laboratory-adapted viruses, are very sensitive, whereas most Tier 2/3 viruses, which are the vast majority of circulating strains, are resistant to Ser5. Notably, native Tier 1 Env trimers predominantly occupy an open conformation, whereas those Tier 2/3 trimers occupy a closed conformation. In addition, Ser5 makes HIV- 1 become sensitive to neutralizing antibodies, suggesting that Ser5 may modify the Env conformation. We hypothesize that Ser5 disrupts Env trimers in an open state, resulting in Env inactivation and blockade of HIV-1 entry. We will use a sensitive bimolecular fluorescence complementation (BiFC) assay to study Env oligomerization and SERINC-Env interactions in live cells and use virologic assays to elucidate how HIV-1 entry is blocked by Ser5 and also likely by Ser4. Second, We will elucidate how Nef antagonizes Ser5. Nef counteracts Ser5 by downregulating Ser5 from plasma membrane and excluding it from virions, but the precise mechanism is still unclear. We reported that Nef rapidly internalizes Ser5 via receptor-mediated endocytosis and re-localizes Ser5 to endosomes. Ser5 is then targeted to lysosomes in a ubiquitination-dependent manner for degradation. Cyclin K (CycK) is a previously identified Nef-binding protein that binds Cyclin-dependent kinase (CDK) 12 and 13 and regulates gene expression and genome stability. We found that CycK and CDK13 are required for Nef-downregulation of Ser5. We hypothesize that Nef recruits CDK13/CycK to plasma membrane to phosphorylate Ser5 and targets Ser5 to endosome/lysosome pathways for degradation. We will study the critical role of the CDK13/CycK complex in Nef downregulation of Ser5 by testing the Ser5 phosphorylation and determine how the phosphorylation affects the Ser5 intracellular trafficking and/or degradation. New antiretroviral mechanisms and/or targets will be discovered from our investigations, which is likely translated into novel antiretroviral therapies.

SERINC5 （Ser5）是一种强烈阻断HIV-1进入的新型限制因子。Ser5属于丝氨酸