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The role of FEZ1 in early HIV-1 infection

FEZ1 在早期 HIV-1 感染中的作用

基本信息

批准号：
10647657
负责人：
Mojgan Hosseini Naghavi
金额：
$ 36.02万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647657
关键词：
Adaptor Signaling Protein Affect Affinity Binding Binding Proteins C-terminal Capsid Cell Line Cell Nucleus Cells Coiled-Coil Domain Collaborations Competitive Binding Complex Coupled Cytoplasm Data Development Dynein ATPase Elongation Factor Equilibrium Event Exhibits Filament Funding HIV Infections HIV-1 Human Image In Vitro Individual Infection Integration Host Factors Kinesin Location Longevity Mediating Microglia Microtubule Stabilization Microtubules Modification Motor Nature Nucleocapsid Outcome Phosphorylation Phosphotransferases Play Plus End of the Microtubule Process Proteins Public Health Resource-limited setting Reverse Transcription Role T-Lymphocyte Testing Universities Viral Viral Genome Work antiretroviral therapy cell motility cell type cofactor design genetic regulatory protein innovation insight mutant novel strategies overexpression particle preference recruit

项目摘要

Although widespread use of combination antiretroviral therapy (cART) has effectively increased the life span of many infected individuals, HIV-1 continues to be a major public health issue in both developed and poor resource settings. As such, understanding the basic mechanisms of its replication cycle is instrumental to the development of new approaches to treat infection. HIV-1 employs unusual, intricately intertwined early infection strategies involving reverse transcription, disassembly of capsid core (also known as “uncoating”) and transport to the nucleus. Although its precise timing and location remain contentious, growing evidence suggests that at least partial uncoating occurs in the cytoplasm during transport to the nucleus. Indeed, incoming HIV-1 particles exhibit microtubule (MT) based bi-directional motility suggestive of their association with both inward (dynein) and outward (kinesin) MT motors, and recent studies suggest that the opposing forces generated by these motors facilitate uncoating. Despite this, HIV-1 does not appear to bind motors directly but instead, uses motor adaptors whose identity remained enigmatic until recent years. Our work funded in the previous cycle identified the HIV-1 kinesin-1 adaptor as Fasiculation and Elongation Factor Zeta 1 (FEZ1). We further established FEZ1’s central role in the transport and uncoating of incoming viral particles in natural target cells, which is regulated through FEZ1 phosphorylation that controls kinesin-1 activity. Moreover, we found that HIV-1 cores bind microtubule associated regulatory kinase 2 (MARK2) to locally control FEZ1 phosphorylation on viral particles. We further showed that HIV-1 particles also bind highly specialized MT regulatory proteins to induce the formation of stable MT networks, a subset of MT filaments favored by kinesin motors. Using innovative structural and functional studies in collaboration with the Xiong Lab at Yale University, our preliminary data reveals an usual and high affinity binding strategy used by HIV-1 to engage FEZ1 for transport that is mediated by capsid hexamers and one of four coiled-coil domains in FEZ1. Data also suggests that FEZ1 and MARK2 compete for binding in a manner that controls the extent of FEZ1 phosphorylation on HIV-1 capsids. In addition, we identify a new host factor that our data suggests binds distinct coiled-coil regions in FEZ1 and is exploited by incoming viral particles to enhance MT stabilization at the cell periphery. Cumulatively, our data suggests that distinct coiled-coil domains in FEZ1 mediate capsid binding, motor recruitment and MT stabilization to coordinate several aspects of early HIV-1 transport and uncoating. In this proposal, we aim to determine how FEZ1 and MARK2 function on the HIV-1 capsid to promote early infection and expand upon our new findings that FEZ1 plays a multifunctional role in early infection by recruiting both motors and regulators of MT stability to incoming HIV-1 particles. The outcome of our studies will provide important mechanistic insights into the multifunctionality of FEZ1 and expand our broader understanding of how HIV-1 controls several important steps in early infection of natural target cells.

虽然抗逆转录病毒联合治疗（cART）的广泛使用有效地延长了患者的寿命

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microtubule plus end-associated CLIP-170 initiates HSV-1 retrograde transport in primary human cells.

DOI：
10.1083/jcb.201505123
发表时间：
2015-10-26
期刊：
The Journal of cell biology
影响因子：
0
作者：
Jovasevic V;Naghavi MH;Walsh D
通讯作者：
Walsh D

Exploitation of Cytoskeletal Networks during Early Viral Infection.

早期病毒感染期间细胞骨架网络的利用。

DOI：
10.1016/j.tim.2018.06.008
发表时间：
2019-01
期刊：
Trends in microbiology
影响因子：
15.9
作者：
Walsh D;Naghavi MH
通讯作者：
Naghavi MH

HIV-1 capsid exploitation of the host microtubule cytoskeleton during early infection.

早期感染过程中宿主微管细胞骨架的HIV-1衣壳剥离。

DOI：
10.1186/s12977-021-00563-3
发表时间：
2021-07-06
期刊：
Retrovirology
影响因子：
3.3
作者：
Naghavi MH
通讯作者：
Naghavi MH

Dynactin 1 negatively regulates HIV-1 infection by sequestering the host cofactor CLIP170.

Dynactin 1 通过隔离宿主辅因子 CLIP170 来负向调节 HIV-1 感染。

DOI：
10.1073/pnas.2102884118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Shanmugapriya,Shanmugapriya;SantosdaSilva,Eveline;Campbell,JacksonA;Boisjoli,Marie-Philipe;Naghavi,MojganH
通讯作者：
Naghavi,MojganH

HIV-1 induces the formation of stable microtubules to enhance early infection.

DOI：
10.1016/j.chom.2013.10.012
发表时间：
2013-11-13
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Sabo Y;Walsh D;Barry DS;Tinaztepe S;de Los Santos K;Goff SP;Gundersen GG;Naghavi MH
通讯作者：
Naghavi MH