HIV-1 Vif protein blocks the cytidine deaminase activity of B-cell specific AID in E. coli by a similar mechanism of action.
HIV-1 Vif protein protects viral replication in non-permissive cells by inducing degradation of APOBEC3G via ubiquitination and proteasomal pathway, although new studies indicate a putative role in Vif's direct inhibition of APOBEC3G. APOBEC3G is member of a homologous family of proteins with cytidine deaminase activity expressed with characteristic tissue specificity, that in humans consist of APOBEC1, APOBEC2, APOBEC3A-H, APOBEC4 and the activation-induced deaminase (AID), a B lymphoid protein necessary for somatic hypermutation, gene conversion and class switch recombination. In this work we show that Vif can counteract AID's activity in E. coli in absence of specific eukaryotic co-factors necessary for AID induced somatic hypermutation, gene conversion and to stimulate class switch recombination in B-cells. We show that AID inhibition is mediated by a direct protein-protein interaction via unique amino acid D118 an homologous mutant responsible for the species-specific restriction of HIV-1 Vif protein existent for APOBEC3G. These results raise the hypothesis that Vif related proteins can act as a broad inhibitor of deaminase activity. Moreover as AID and Vif evolved in different cellular environments, these results may indicate that Vif related proteins might mimic cellular factors that interact with a structural conserved domain of cytidine deaminases during evolution.
URIA-Centro de Patogénese Molecular, Faculdade de Farmácia, Universidade de Lisboa, 1649-019 Lisboa, Portugal.
Mariana
M
Santa-Marta
Frederico
F
Aires da Silva
Ana Margarida
AM
Fonseca
Sylvie
S
Rato
Joao
J
Goncalves
D000071480:APOBEC-3G Deaminase; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000821:virology; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000235:genetics; D004926:Escherichia coli; D016346:Gene Products, vif / Q000235:genetics* / Q000378:metabolism; D015322:Gene Rearrangement, B-Lymphocyte; D015497:HIV-1; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D054320:vif Gene Products, Human Immunodeficiency Virus; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016346:Gene Products, vif; D012097:Repressor Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D009700:Nucleoside Deaminases; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase