Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif

Land, Allison M.; Wang, Jiayi; Law, Emily K.; Aberle, Ryan; Kirmaier, Andrea; Krupp, Annabel; Johnson, Welkin E.; Harris, Reuben S.

doi:10.18632/oncotarget.5483

Cited by 17 publications

(27 citation statements)

References 55 publications

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“…As a positive control, SIV Vif caused the degradation of human A3G, and this effect could be partly reversed by MG132 which blocks proteosomal processing. SIV Vif also mediated the degradation of human A3B, as reported (Land et al, 2015), and this effect could also be suppressed by MG132. In contrast, K-free A3B was unaffected by SIV Vif expression or MG132 treatment.…”

Section: Resultssupporting

confidence: 78%

“…Despite the inability of HIV-1 Vif to degrade human A3B, the Vif protein of multiple SIV strains is active for human A3B degradation (Land et al, 2015). Vif-mediated degradation of A3 enzymes occurs mainly by poly-ubiquitination of lysine residues and subsequent processing by the 26S proteasome [reviewed by (Harris and Dudley, 2015; Malim and Bieniasz, 2012; Simon et al, 2015)].…”

Section: Resultsmentioning

confidence: 99%

“…The K-free A3B construct was ordered as a G-Block from IDT where all 10 lysine residues were mutated to arginines and subsequently cloned into an untagged expression vector pcDNA 3.1 (+) or into pEGFP-N3 (Clontech). The untagged A3B catalytic mutant (CM) construct encoding two glutamate to alanine amino acid substitutions (E68A/E255A) was PCR amplified from existing pEGFP-N3 (Clontech) plasmids described previously (Burns et al, 2013; Hultquist et al, 2011; Lackey et al, 2013; Land et al, 2015) using primers NNNAAGCTTACCGCCATGAATCCACAGATC and NNNNGCGGCCGCTCAGTTTCCCTGATTCTGGAGAATGG. PCR products were then digested with restriction enzymes Hind III-HF and Not I-HF in CutSmart Buffer (NEB #R3104S and #R3189S respectively).…”

Section: Methodsmentioning

confidence: 99%

“…However, multiple studies have shown that A3B can potently restrict HIV-1 in 293T cells (Bishop et al, 2004; Doehle et al, 2005; Hultquist et al, 2011), whereas it cannot in various T-cell lines (Hultquist et al, 2011). Further complicating the story, human A3B can be targeted for protesomal degradation by SIV Vif leading to the possibility that A3B may still be relevant in some situations or, at the very least, was relevant in primate ancestors (Land et al, 2015). To better understand how and why A3B is able to restrict HIV-1 in some cell types but not others, and evade some but not all retroviral Vif proteins, we investigated mechanisms responsible for A3B post-translational regulation.…”

Section: Introductionmentioning

confidence: 99%

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APOBEC3B lysine residues are dispensable for DNA cytosine deamination, HIV-1 restriction, and nuclear localization

et al. 2017

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The APOBEC3 DNA cytosine deaminase family comprises a fundamental arm of the innate immune response and is best known for retrovirus restriction. Several APOBEC3 enzymes restrict HIV-1 and related retroviruses by deaminating viral cDNA cytosines to uracils compromising viral genomes. Human APOBEC3B (A3B) shows strong virus restriction activities in a variety of experimental systems, and is subjected to tight post-translational regulation evidenced by cell-specific HIV-1 restriction activity and active nuclear import. Here we ask whether lysines and/or lysine post-translational modifications are required for these A3B activities. A lysine-free derivative of human A3B was constructed and shown to be indistinguishable from the wild-type enzyme in DNA cytosine deamination, HIV-1 restriction, and nuclear localization activities. However, lysine loss did render the protein resistant to degradation by SIV Vif. Taken together, we conclude that lysine side chains and modifications thereof are unlikely to be central to A3B function or regulation in human cells.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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APOBEC3B lysine residues are dispensable for DNA cytosine deamination, HIV-1 restriction, and nuclear localization

et al. 2017

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“…Human A3B is a potent inhibitor against HIV-1, SIV, and human T cell leukemia virus (HTLV) (19,(29)(30)(31)(32). In addition, human A3B was reported to be upregulated in several cancer cells and found to be degraded by virion infectivity factor (Vif) from several SIV lineages (33)(34)(35)(36)(37)(38)(39).…”

Section: S Imian Immunodeficiency Virus (Siv) Naturally Infects Manymentioning

confidence: 99%

Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C

Zhang

Vasudevan

et al. 2016

J Virol

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Lentiviruses have evolved the Vif protein to counteract APOBEC3 (A3) restriction factors by targeting them for proteasomal degradation. Previous studies have identified important residues in the interface of human immunodeficiency virus type 1 (HIV-1) Vif and human APOBEC3C (hA3C) or human APOBEC3F (hA3F). However, the interaction between primate A3C proteins and HIV-1 Vif or natural HIV-1 Vif variants is still poorly understood. Here, we report that HIV-1 Vif is inactive against A3Cs of rhesus macaques (rhA3C), sooty mangabey monkeys (smmA3C), and African green monkeys (agmA3C), while HIV-2, African green monkey simian immunodeficiency virus (SIVagm), and SIVmac Vif proteins efficiently mediate the depletion of all tested A3Cs. We identified that residues N/H130 and Q133 in rhA3C and smmA3C are determinants for this HIV-1 Vif-triggered counteraction. We also found that the HIV-1 Vif interaction sites in helix 4 of hA3C and hA3F differ. Vif alleles from diverse HIV-1 subtypes were tested for degradation activities related to hA3C. The subtype F-1 Vif was identified to be inactive for degradation of hA3C and hA3F. The residues that determined F-1 Vif inactivity in the degradation of A3C/A3F were located in the C-terminal region (K167 and D182). Structural analysis of F-1 Vif revealed that impairing the internal salt bridge of E171-K167 restored reduction capacities to A3C/A3F. Furthermore, we found that D101 could also form an internal interaction with K167. Replacing D101 with glycine and R167 with lysine in NL4-3 Vif impaired its counteractivity to A3F and A3C. This finding indicates that internal interactions outside the A3 binding region in HIV-1 Vif influence the capacity to induce degradation of A3C/A3F. IMPORTANCEThe APOBEC3 restriction factors can serve as potential barriers to lentiviral cross-species transmissions. Vif proteins from lentiviruses counteract APOBEC3 by proteasomal degradation. In this study, we found that monkey-derived A3C, rhA3C and smmA3C, were resistant to HIV-1 Vif. This was determined by A3C residues N/H130 and Q133. However, HIV-2, SIVagm, and SIVmac Vif proteins were found to be able to mediate the depletion of all tested primate A3C proteins. In addition, we identified a natural HIV-1 Vif (F-1 Vif) that was inactive in the degradation of hA3C/hA3F. Here, we provide for the first time a model that explains how an internal salt bridge of E171-K167-D101 influences Vif-mediated degradation of hA3C/hA3F. This finding provides a novel way to develop HIV-1 inhibitors by targeting the internal interactions of the Vif protein. S imian immunodeficiency virus (SIV) naturally infects manyOld World primate species in Africa. The pandemic of human immunodeficiency virus (HIV) originated from cross-species transmission events of SIVs to humans. HIV-1 was introduced into the human population by multiple transmissions of a chimpanzee (cpz) virus, which is known as SIVcpz. The less virulent human lentivirus, HIV-2, was derived from SIVsmm, which was obtained from sooty mangabey monkeys (sm...

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Assessment of an APOBEC3B truncating mutation, c.783delG, in patients with breast cancer

Radmanesh

Spethmann

Enßen

et al. 2017

Breast Cancer Res Treat

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Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif

Cited by 17 publications

References 55 publications

APOBEC3B lysine residues are dispensable for DNA cytosine deamination, HIV-1 restriction, and nuclear localization

APOBEC3B lysine residues are dispensable for DNA cytosine deamination, HIV-1 restriction, and nuclear localization

Vif Proteins from Diverse Human Immunodeficiency Virus/Simian Immunodeficiency Virus Lineages Have Distinct Binding Sites in A3C

Assessment of an APOBEC3B truncating mutation, c.783delG, in patients with breast cancer

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