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

Li Zhu,Yukang Yuan,Zhenke Wen,Chuanwu Zhu,Hui Zheng,Feng Qian,Fan Huang,Hong-Guang Zhang,Jing Guo,Tengfei Ren,Jin Liu,Xiangjie Chen,Weifeng Shi,Yibo Zuo,Ying Miao,Chunsheng Dong,Jiuyi He,Lincong Jin

doi:10.3389/fmicb.2020.597972

Abstract

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.

Highlights

In the long-term process of virus evolution, human immunodeficiency virus-1 (HIV-1) has developed many strategies to escape the immunosuppression of the host, which facilitates virus survival and subsequent replication (Strebel, 2013; Seissler et al, 2017; Yin et al, 2020)
These findings suggested that HIV-1 Nef protein could interact with cellular ubiquitin E3 ligase c-Cbl
HIV-1 Nef has been demonstrated to be involved in downregulating a number of host proteins to antagonize immune responses

Summary

Introduction

In the long-term process of virus evolution, human immunodeficiency virus-1 (HIV-1) has developed many strategies to escape the immunosuppression of the host, which facilitates virus survival and subsequent replication (Strebel, 2013; Seissler et al, 2017; Yin et al, 2020). Among these strategies, HIV-1-encoded proteins widely hijack the signaling transduction activities of the host cells, and destroy the host immune defense to resist host antiviral responses. These findings uncover the roles of HIV-1 Nef in downregulating host proteins, how HIV-1 Nef protein is downregulated by host factors remains largely unexplored

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Results

Conclusion