Ubiquitin E3 Ligase c-Cbl Is a Host Negative Regulator of Nef Protein of HIV-1

Nef is an accessory protein encoded by human immunodeficiency virus type-1 (HIV-1) and plays important roles in regulating HIV-1 infection and viral replication. Interestingly, HIV-1 Nef can promote degradation of numerous host proteins to disrupt cellular antiviral immune response. However, how HIV...

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Published inFrontiers in microbiology Vol. 11; p. 597972
Main Authors Zhang, Hong-Guang, Guo, Jing, Yuan, Yukang, Zuo, Yibo, Liu, Jin, Zhu, Li, Miao, Ying, Chen, Xiangjie, Jin, Lincong, Huang, Fan, Ren, Tengfei, He, Jiuyi, Shi, Weifeng, Wen, Zhenke, Zhu, Chuanwu, Zheng, Hui, Dong, Chunsheng, Qian, Feng
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 19.11.2020
Subjects
c-Cbl
E3 ubiquitin ligase
HIV-1
Microbiology
Nef
ubiquitination
HIV-1
E3 ubiquitin ligase
c-Cbl
ubiquitination
Nef
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Summary:Nef is an accessory protein encoded by human immunodeficiency virus type-1 (HIV-1) and plays important roles in regulating HIV-1 infection and viral replication. Interestingly, HIV-1 Nef can promote degradation of numerous host proteins to disrupt cellular antiviral immune response. However, how HIV-1 Nef is degraded by host factors remains largely unexplored. Here, we identified c-Cbl as a host ubiquitin E3 ligase of HIV-1 Nef. We found that c-Cbl interacts with Nef and reduces protein levels of HIV-1 Nef. Further studies demonstrated that c-Cbl promoted Lys48-linked polyubiquitination of HIV-1 Nef, thus attenuating protein stability of HIV-1 Nef. Importantly, cellular c-Cbl ubiquitinated and degraded Nef proteins produced by HIV-1 NL4-3 virions, and ultimately attenuated HIV-1 virulence for infection of THP1 cells. This study reveals a ubiquitination and proteasome-dependent degradation mechanism of HIV-1 Nef protein, and could provide potential strategies for fighting against HIV-1.
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Reviewed by: Mikako Fujita, Kumamoto University, Japan; Akifumi Takaori-Kondo, Kyoto University, Japan; Michael Bukrinsky, George Washington University, United States
Edited by: Akio Adachi, Kansai Medical University, Japan
These authors have contributed equally to this work
This article was submitted to Virology, a section of the journal Frontiers in Microbiology
ISSN:1664-302X
1664-302X
DOI:10.3389/fmicb.2020.597972