The APOBEC3 family of retroelement restriction factors

Abstract

The ability to regulate and even target mutagenesis is an extremely valuable cellular asset. Enzyme-catalyzed DNA cytosine deamination is a molecular strategy employed by vertebrates to promote antibody diversity and defend against foreign nucleic acids. Ten years ago, a family of cellular enzymes was first described with several proving capable of deaminating DNA and inhibiting HIV-1 replication. Ensuing studies on the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) restriction factors have uncovered a broad-spectrum innate defense network that suppresses the replication of numerous endogenous and exogenous DNA-based parasites. Although many viruses possess equally elaborate counter-defense mechanisms, the APOBEC3 enzymes offer a tantalizing possibility of leveraging innate immunity to fend off viral infection. Here, we focus on mechanisms of retroelement restriction by the APOBEC3 family of restriction enzymes, and we consider the therapeutic benefits, as well as the possible pathological consequences, of arming cells with active DNA deaminases.

Fig. 1

Evolution and structure-function of APOBEC cytosine deaminases. (a) Expansion of the modern primate APOBEC3 locus encoding seven APOBEC3 genes with eleven zinc-coordinating (Z) domains [reprinted with permission from (Lackey et al. 2012)]. (b) Deamination of cytosine to uracil plays a central role in innate immunity. (c) Three-dimensional structures of the APOBEC3G C-terminal domain and APOBEC3C. A zinc ion (purple) is shown coordinated in both proteins by one histidine and two cysteine residues in the α2-β3-α3 core.

Fig. 2

The physiological functions of the APOBEC family. (a) RNA editing by APOBEC1 generates a truncated APOB protein. (b) AID activity underpins the processes of somatic hypermutation and class switch recombination in B-cell germinal centers. (c) Four APOBEC3 proteins restrict HIV through cytosine deamination in the absence of Vif [reprinted with permission from (Hultquist et al. 2011)].

Fig. 3

APOBEC expression and model of carcinogenesis. (a) APOBEC family mRNA expression in the indicated cell lines and normal human tissues. Data are relative to levels of AID in the spleen [reprinted with permission from (Burns et al. 2013)]. (b) Model depicting the effect of APOBEC3B overexpression over time.

Fig. 4

Potential therapies harnessing APOBEC3 innate immunity. (a) Inhibition of the Vif-E3 ligase complex could result in virus restriction. (b) Inhibiting the deaminase activity of APOBEC3 proteins could deprive HIV of a source of variation and allow immune clearance.