Regulatory Mimicry of Cyclin-Dependent Kinases by Conserved Herpesvirus Protein Kinases
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Abstract
Herpesviruses encode conserved protein kinases (CHPKs) that target cellular cyclin-dependent kinase (CDK) phosphorylation sites; thus, they are termed viral CDK-like kinases. Tyrosine 15 in the GxGxxG motifs of CDK1 and CDK2, whose phosphorylation down-regulates their catalytic activities, is conserved in the corresponding motifs of CHPKs. We found that herpes simplex virus 2 (HSV-2) CHPK UL13 mimicked the regulatory mechanism of CDKs. This regulatory mimicry was conserved in CHPKs encoded by herpesviruses subclassified into subfamilies other than HSV-2, suggesting CHPKs have regulatory and functional mimicry with CDKs. Phosphorylation of the corresponding Tyr in HSV-2 UL13 was required for the down-regulation of viral replication and pathogenicity, specifically in the central nervous system of mice, and for efficient viral recurrence in guinea pigs. These data highlight the dual impact of the regulatory mimicry of CDKs by CHPK on the fine-tuned regulation of lytic and latent HSV-2 infections in vivo .
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Interestingly, the corresponding Tyrs in the GxGxxG motif of CDKs and CHPKs are also well conserved in F10L homologs, viral kinases encoded by poxviruses, but not in other viral kinases including B1R homologs of poxviruses and Us3 homologs of alphaherpesviruses7 (S-Fig. 9), suggesting poxviruses might have also evolved CDK regulatory mimicry by conserved F10L kinases.
I'm curious if you've thought about how viruses acquired this motif. It's short enough that it could have occurred in both herpes and pox viruses via convergent evolution of an existing kinase. However, many proteins in both herpes and pox viruses were acquired from hosts via horizontal gene transfer, so it's plausible this kinase could have been as well and that the motif was conserved. Are there clues from other domains in the protein or other viral kinases about the …
Interestingly, the corresponding Tyrs in the GxGxxG motif of CDKs and CHPKs are also well conserved in F10L homologs, viral kinases encoded by poxviruses, but not in other viral kinases including B1R homologs of poxviruses and Us3 homologs of alphaherpesviruses7 (S-Fig. 9), suggesting poxviruses might have also evolved CDK regulatory mimicry by conserved F10L kinases.
I'm curious if you've thought about how viruses acquired this motif. It's short enough that it could have occurred in both herpes and pox viruses via convergent evolution of an existing kinase. However, many proteins in both herpes and pox viruses were acquired from hosts via horizontal gene transfer, so it's plausible this kinase could have been as well and that the motif was conserved. Are there clues from other domains in the protein or other viral kinases about the origin of this motif?
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UL13 homologs inhibit various cellular signaling pathways including JAK/STAT, RIG-I-like receptor, and cGAS/STING39–42.
Is this regulation via the same motif/tyrosine?
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HSV-2 UL13
It would be helpful to know at this point if UL13 is the only CHPK in HSV-2
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