The Role of APOBECs in Viral Replication

Abstract

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to selection for viral variants.

Mutational signatures reveal ternary relationships between homologous recombination repair, APOBEC, and mismatch repair in gynecological cancers

“…Dysregulation of physiological mutagenesis processes in cancer cells may also contribute to accumulation of mutations. For example, aberrant activity of APOBEC enzymes, which are involved in protection against viral infections, has been shown as a major source of mutations in multiple human cancer types [ 27 , 28 ], including bladder, cervix, lung, head and neck, and breast [ 4 , 17 , 29 – 31 ]. Currently, ABOBEC3A and APOBEC3B are the main family members implicated in cancer [ 31 , 32 ], and SBS2 and SBS13 are mutational signatures associated with APOBEC-mediated mutagenesis [ 4 , 17 ].…”

Inhibition of base editors with anti-deaminases derived from viruses

“…Additionally, we evaluated their inhibitory effect on three A3 deaminases from other species, including RmA3Bctd (rhesus monkey), mA3CDA1 26 (mouse) and SsA3Bctd 27 ( Sus scrofa ). These Ades did not show an inhibitory effect on the tested deaminases, except for Ade1, which slightly inhibited RmA3Bctd-CBE, suggesting that these Ades are species-specific and mainly evolved to inhibit human A3 deaminases 15 (Supplementary Fig. 1 ).…”

“…1a ). The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses 15 , 16 . As a countermeasure, viruses have evolutionarily acquired a series of genes to inhibit the antiviral activity of APOBEC3 proteins 16 .…”

APOBECs orchestrate genomic and epigenomic editing across health and disease

“…APOBEC deaminases further restrict DNA viruses and retroviruses directly in an editingdependent manner (extensively reviewed in [48]) (Figure 3A). Recently, studies on coronaviruses (CoVs) and rubella also indicated an involvement of APOBECs in RNA virus restriction.…”

“…The contribution of APOBECs to host-virus coevolution is under investigation, and whether APOBEC-induced mutations contribute to immune escape or drug resistance of the virus has been debated (Box 1). Apart from APOBEC-mediated virus genome editing, various publications report deaminationindependent restriction mechanisms, and APOBECs may therefore interfere with the replication and transcription of viral genomes by binding to viral proteins and RNAs or by blocking viral polymerases (reviewed in [48]).…”