Structural Insights into APOBEC3-Mediated Lentiviral Restriction

Abstract

Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins—A3G, A3F, A3H, and A3D—restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.

Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution

“…Human Immunodeficiency Virus (HIV-1). The inhibition of HIV-1 replication through the function of A3D, A3F, A3G, and A3H is the most extensively studied of the viral restriction phenotype of the APOBEC family and has been well reviewed elsewhere ( Aydin et al, 2014 ; Delviks-Frankenberry et al, 2020 ; Desimmie et al, 2014 ; Haché et al, 2006 ; Harris and Dudley, 2015 ; Xu et al, 2020 ). During production of new virions in a productively infected host cell, A3 proteins form ribonucleoprotein complexes with HIV-1 RNA and the nucleocapsid domain of the Gag protein.…”

Deaminase-Independent Mode of Antiretroviral Action in Human and Mouse APOBEC3 Proteins

“…All APOBEC3s contain one or two cytidine deaminase domains (CDs), which are also called zinc-coordinating domains (Z-domains), that consist of H-X-E-X 25–31 -C-X 2–4 -C, where X represents any amino acid ( Figure 1 ) [ 59 , 62 , 102 ]. The Z-domains can be further classified into three types, Z1, Z2, or Z3 based on characteristic amino acids in these domains [ 62 ].…”

APOBEC3s: history of an antiviral and mutagenic protein family

“…Lors de la désamination, une molécule d'eau coordinée dans le site actif par un ion Zn 2+ est déprotonée en ion hydroxyde qui va réagir avec le carbone C4 de la cytosine. Cette attaque est suivie d'un transfert de proton entre l'acide glutamique et l'azote N3 de la cytosine et finalement par l'élimination d'une molécule d'ammoniac et la formation du carbonyle en C4 (figure 2B) [12,26]. xMx [3][4] xMx 3 Les ZDD caractéristiques des différents groupes phylogénétiques des A3 sont représentées en couleur, les séquences en acides aminés correspondantes sont détaillées au bas de la figure (adaptées de [22]).…”