Abstract
The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded (ss)DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes—APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new pathogen-host conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.
Highlights
ICP10 are mediated by the N-terminal RIP homotypic interaction motif (RHIM) domain and C-terminal ribonucleotide reductase (RNR) large subunit domain, which interact with receptor-interacting kinases (RIP1 and RIP3) and caspase-8, respectively, to prevent necrosome formation and apoptosis
An herpes simplex virus-1 (HSV-1) variant with two point mutations in the RNR large subunit showed severely compromised infectivity in a humanized mouse model, suggesting greater importance in vivo [48]. These observations, along with the recent discovery of the novel A3B counteraction function of Epstein-Barr virus (EBV) BORF2 [21], raised the question of whether or not A3 antagonism is a conserved function of all herpesvirus RNR large subunits
Several distinct mechanisms have been defined including A3 occlusion, A3 aggregation, A3 avoidance
Summary
DNA polymerase; BORF2, viral ribonucleotide reductase large genome the nucleus, acquisition of a lipid bilayer envelope in the cytoplasm, subsequent release from the cellular subunit;inBMRF1, the viral processivity factor). Ribonucleotide reductase enzymes (RNRs) catalyze the conversion of nucleoside dienters the nucleus, circularizes, and forms a stable extrachromosomal episome, which undergoes methylation, histone modification, and chromatinization [1,2,4] This process serves to disguise the viral genome as cellular DNA [5] and determines whether the initial infection adopts a latent or lytic replication mode [6,7]. Herpesvirus genomes do not typically exhibit C/G-to-T/A mutations characteristic of APOBEC editing and, until recently, this observation was attributed to the protection afforded by chromatinization and the utilization of high-fidelity DNA replication mechanisms
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