Translational regulation of APOBEC3G mRNA by Vif requires its 5′UTR and contributes to restoring HIV-1 infectivity

Guerrero, Santiago; Libre, Camille; Batisse, Julien; Mercenne, Gaëlle; Richer, Delphine; Laumond, Géraldine; Decoville, Thomas; Moog, Christiane; Marquet, Roland; Paillart, Jean-Christophe

doi:10.1038/srep39507

Cited by 19 publications

(35 citation statements)

References 60 publications

(85 reference statements)

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“…Interestingly, it has been reported that the Vif mediated A3G inhibition is not only mediated by proteosomal degradation but also by translational repression (Stopak et al, 2003; Guerrero et al, 2016). Though it remains unclear how important each of these pathways are relative to one another in vivo , these findings suggested that both pathways could be targeted to restore cellular A3G levels.…”

Section: Discussionmentioning

confidence: 99%

Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association

Fukuda

Sardo

et al. 2019

Front. Cell. Infect. Microbiol.

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APOBEC3G (A3G) is a cellular protein that inhibits HIV-1 infection through virion incorporation. The interaction of the A3G N-terminal domain (NTD) with RNA is essential for A3G incorporation in the HIV-1 virion. The interaction between A3G-NTD and RNA is not completely understood. The A3G-NTD is also recognized by HIV-1 Viral infectivity factor (Vif) and A3G-Vif binding leads to A3G degradation. Therefore, the A3G-Vif interaction is a target for the development of antiviral therapies that block HIV-1 replication. However, targeting the A3G-Vif interactions could disrupt the A3G-RNA interactions that are required for A3G's antiviral activity. To better understand A3G-RNA binding, we generated in silic o docking models to simulate the RNA-binding propensity of A3G-NTD. We simulated the A3G-NTD residues with high RNA-binding propensity, experimentally validated our prediction by testing A3G-NTD mutations, and identified structural determinants of A3G-RNA binding. In addition, we found a novel amino acid residue, I26 responsible for RNA interaction. The new structural insights provided here will facilitate the design of pharmaceuticals that inhibit A3G-Vif interactions without negatively impacting A3G-RNA interactions.

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Section: Discussionmentioning

confidence: 99%

Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association

Fukuda

Sardo

et al. 2019

Front. Cell. Infect. Microbiol.

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“…The primer sets for this study. in the past, new host-virus relations came to be understood by through these molecules (22,23). Previously it has been reported that multiple APOBEC3 enzymes may limit the infectivity of HTLV-1 (24,25).…”

Section: Discussionmentioning

confidence: 99%

Induction of APOBEC3B cytidine deaminase in HTLV‑1‑infected humanized mice

et al. 2019

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Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). Following viral infection with HTLV-1, certain infected cells exhibit clonal proliferation. Additional genetic and epigenetic changes in these clonally proliferating cells provide them with the selective advantage of growth, which eventually results in ATL. The precise mechanism, however, has yet to be completely elucidated. It has previously been established that APOBEC3 enzymes are potent host-antiviral restriction factors. Conversely, previous studies have reported that the A3B level is increased in tumor virus infections, such as those caused by HBV and HPV, suggesting that A3B exerts a function as a mutagen. Therefore, the present study analyzed the expression of APOBEC3 family members in various HTLV-1 infection states. No significant differences were observed in the expression between healthy donors and patients with HTLV-1-associated myelopathy. Although no significant changes in the expressions of A3C, A3D, A3F and A3G between uninfected and HTLV-1-infected mice were observed, an increased A3B expression was observed in a short-term humanized mouse model following HTLV-1 infection. In a long-term humanized mouse model following HTLV-1 infection, the gene expression array data exhibited an apparent increase in A3B and CADM1, which are indicators of ATL. Collectively, the results of the present study suggest that A3B is likely involved in the development of ATL in HTLV-1-infected humanized mice.

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“…Moreover, by sequestering CBF-β in the E3-ubiquitin ligase complex, Vif indirectly causes a decrease in A3G transcription as the A3G gene is regulated by the RUNX transcription factor family, which requires CBF-β as cofactor ( Figure 4 C①) [ 81 ]. Degradation of A3G through the UPS has been known for a long time as the main mechanism for HIV-1 to counteract cellular restriction; however it has been shown that Vif can also inhibit A3G translation [ 82 , 112 , 113 ] and this inhibition significantly contributes to the counteraction mechanism ( Figure 4 C②) [ 82 , 112 , 113 ]. While A3G is the main member of the A3-family that efficiently restricts HIV, A3D, F and H also showed a restricting activity towards HIV-1 in the absence of Vif, even though to a lesser extent than A3G [ 114 ].…”

Section: Counteraction Of Restriction Factors By Viral Auxiliary Pmentioning

confidence: 99%

Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins

Seissler

Marquet

Paillart

2017

Viruses

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The ubiquitin-proteasome system (UPS) ensures regulation of the protein pool in the cell by ubiquitination of proteins followed by their degradation by the proteasome. It plays a central role in the cell under normal physiological conditions as well as during viral infections. On the one hand, the UPS can be used by the cell to degrade viral proteins, thereby restricting the viral infection. On the other hand, it can also be subverted by the virus to its own advantage, notably to induce degradation of cellular restriction factors. This makes the UPS a central player in viral restriction and counter-restriction. In this respect, the human immunodeficiency viruses (HIV-1 and 2) represent excellent examples. Indeed, many steps of the HIV life cycle are restricted by cellular proteins, some of which are themselves components of the UPS. However, HIV itself hijacks the UPS to mediate defense against several cellular restriction factors. For example, the HIV auxiliary proteins Vif, Vpx and Vpu counteract specific restriction factors by the recruitment of cellular UPS components. In this review, we describe the interplay between HIV and the UPS to illustrate its role in the restriction of viral infections and its hijacking by viral proteins for counter-restriction.

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Translational regulation of APOBEC3G mRNA by Vif requires its 5′UTR and contributes to restoring HIV-1 infectivity

Cited by 19 publications

References 60 publications

Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association

Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association

Induction of APOBEC3B cytidine deaminase in HTLV‑1‑infected humanized mice

Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins

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