Differential Contributions of Ubiquitin-Modified APOBEC3G Lysine Residues to HIV-1 Vif-Induced Degradation

Turner, Tiffany M; Shao, Qiujia; Wang, Weiran; Wang, Yudi; Wang, Chenliang; Kinlock, Ballington L.; Liu, Bindong

doi:10.1016/j.jmb.2016.05.029

Cited by 10 publications

(11 citation statements)

References 49 publications

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“…As the ubiquitination of A3G depends on the type of K48, we overexpressed K48 ubiquitin and confirmed that the ubiquitination of A3G is regulated by USP49. However, we found that the K48-linked ubiquitination was suppressed when the mutant K48R was used (Figure 4F), which is consistent with previous studies (Mehle et al, 2004; Turner et al, 2016).…”

Section: Resultssupporting

confidence: 92%

“…This pathway occurs via the UPS as MG132 could also block the degradation and ubiquitination of A3G. This phenomenon could explain why there are some ubiquitination sites on A3G that are not located at the C-terminus of A3G and not regulated by Vif (Albin et al, 2013; Iwatani et al, 2009; Turner et al, 2016). We attempted to identify the host E3 protein(s) that could be involved in A3G ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

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

Pan

Zheng

et al. 2019

eLife

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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.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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

Pan

Zheng

et al. 2019

eLife

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“…The finding that MG132 increases expression of haplotypes III and IV to levels at or exceeding that of haplotype I ( Figure 1A) prompted us to investigate if restoring expression of N15del haplotypes would lead to an increase in antiviral activity. As MG132 has pleotropic effects and precludes reliable results from our infectivity assays, we employed the lysine mutagenesis approach previously used to study Vif-mediated polyubiquitination of A3G [34][35][36]. In order to prevent polyubiquitination of A3H, we converted each of the 14 lysines (K) in A3H to arginine (Figure 2A).…”

Section: Rates Of Ubiquitination Differ Among A3h Haplotypesmentioning

confidence: 99%

Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity

Chesarino

Emerman

2020

Viruses

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The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like Human Immunodeficiency Virus (HIV). APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant of A3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). In this paper, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification. Inhibiting ubiquitination by mutating all of the A3H lysines increased the expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity. Fusion chimeras with haplotype II allowed for stabilization, cytoplasmic retention, and packaging of the N15del-containing haplotype III, but the haplotype III component of these chimeras was unable to restrict HIV-1 on its own. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability.

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“…This initial ubiquitylation then accelerates polyubiquitylation by UBE2R1, but is not essential for A3G ubiquitylation [184]. Ubiquitylation occurred on lysine residues throughout A3G N-and C-terminal regions [189,190]. Although both N-and C-terminal regions of A3G can be polyubiquitylated, the Nterminal domain contributes less to Vif-mediated proteasomal degradation [190].…”

Section: A3-mediated Hypermutation In Hiv-1-infected Patientsmentioning

confidence: 99%

“…Ubiquitylation occurred on lysine residues throughout A3G N-and C-terminal regions [189,190]. Although both N-and C-terminal regions of A3G can be polyubiquitylated, the Nterminal domain contributes less to Vif-mediated proteasomal degradation [190]. Consequently, substitutions of lysine to arginine in the A3G C-terminal domain increased A3G resistance to Vif and blocked HIV-1 replication [190].…”

Section: A3-mediated Hypermutation In Hiv-1-infected Patientsmentioning

confidence: 99%

The Role of APOBECs in Viral Replication

Xu¹,

Byun²,

Dudley³

2020

Preprint

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Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to selection for viral variants.

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Differential Contributions of Ubiquitin-Modified APOBEC3G Lysine Residues to HIV-1 Vif-Induced Degradation

Cited by 10 publications

References 49 publications

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

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

Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity

The Role of APOBECs in Viral Replication

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