Abstract
Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic ‘arms races’ with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in ‘housekeeping’ functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.
Highlights
Post-translational modifications (PTMs) of proteins regulate a wide variety of cellular processes, including several aspects of innate immunity against pathogens
At least five primate PARP genes have evolved under recurrent positive selection Motivated by our hypothesis that ADP-ribosylation may be an important PTM in host-virus conflicts, and our prior use of positive selection analyses to identify an important antiviral domain in PARP13, we investigated whether any of the other 16 human PARP genes show signatures of recurrent positive selection
In addition to confirming our earlier findings on PARP13, we found that PARP4 and the three macrodomain-containing PARP genes (PARP9/BAL1, PARP14/BAL2 and PARP15/BAL3) all show signatures of positive selection
Summary
Post-translational modifications (PTMs) of proteins regulate a wide variety of cellular processes, including several aspects of innate immunity against pathogens. Pathogens have evolved mechanisms to block, reverse or usurp this machinery in order to successfully replicate within their hosts [1]. Numerous viruses subvert the dynamics of phosphorylation, employing kinases, substrate mimics and phosphatases to disrupt host signaling [1]. Several viral classes encode proteins to disrupt host phosphorylation and acetylation [2]. Beyond small-molecule PTMs, conjugation and cleavage of ubiquitin and ubiquitin-like molecules has emerged as an important point of cellular regulation that several viruses target or subvert in order to replicate [3]
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