USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication.

Ting Pan,Xiaoping Tang,Ryan Huang,Xuanhong Zhang,Linghua Li,Liyang Wu,Xuemei Ling,Liting Liang,Mo Zhou,Xiancai Ma,Guangyan Liu,Zhilin Peng,Kai Deng,Yonghong Li,Bingfeng Liu,Junsong Zhang,Weiping Cai,Jiacong Zhao,Hui Zhang,Jun Li ,Yong Luo ,Sifa Zheng

doi:10.7554/elife.48318

Abstract

The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.

Highlights

Human apolipoprotein-B-mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) is a member of the cellular polynucleotide cytidine deaminase family. It can be incorporated into vifdeficient human immunodeficiency virus type1 (HIV-1) virions and mediates C–U conversion in the newly synthesized minus-stranded human immunodeficiency virus type 1 (HIV-1) DNA to trigger the breakage of viral DNA or the generation of G-to A lethal hypermutations, resulting in a premature stop codon or mutated viral protein (Harris et al, 2003; Mangeat et al, 2003; Sheehy et al, 2002; Zhang et al, 2003)
It has been shown that USP49 interacts with p53, dual-specificity protein phosphatases (DUSP), or FKBP51 in the nucleus, and suppresses the ubiquitination of these proteins (Luo et al, 2017; Tu et al, 2018; Zhang et al, 2019)
Our data indicate that USP49 is mainly distributed in the nucleus, it exists in the cytoplasm

Summary

Introduction

Human apolipoprotein-B-mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) is a member of the cellular polynucleotide cytidine deaminase family It can be incorporated into vifdeficient human immunodeficiency virus type (HIV-1) virions and mediates C–U conversion in the newly synthesized minus-stranded HIV-1 DNA to trigger the breakage of viral DNA or the generation of G-to A lethal hypermutations, resulting in a premature stop codon or mutated viral protein (Harris et al, 2003; Mangeat et al, 2003; Sheehy et al, 2002; Zhang et al, 2003). A3G can physically block the reverse transcription process (Bishop et al, 2008; Iwatani et al, 2007; Pollpeter et al, 2018) Because of these combined effects, A3G exerts potent antiviral activity. It induces sub-lethal hypermutations, which would not significantly impair viral infectivity but indicate an important driving force for HIV-1 genetic variations.

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