Systematic profiling of protein complex dynamics reveals DNA-PK phosphorylation of IFI16 en route to herpesvirus immunity.

TitleSystematic profiling of protein complex dynamics reveals DNA-PK phosphorylation of IFI16 en route to herpesvirus immunity.
Publication TypeJournal Article
Year of Publication2021
AuthorsJustice, JL, Kennedy, MA, Hutton, JE, Liu, D, Song, B, Phelan, B, Cristea, IM
JournalSci Adv
Volume7
Issue25
Date Published2021 06
ISSN2375-2548
KeywordsHerpes Simplex, Herpesviridae, Herpesviridae Infections, Herpesvirus 1, Human, Host-Pathogen Interactions, Humans, Nuclear Proteins, Phosphoproteins, Phosphorylation
Abstract

<p>Dynamically shifting protein-protein interactions (PPIs) regulate cellular responses to viruses and the resulting immune signaling. Here, we use thermal proximity coaggregation (TPCA) mass spectrometry to characterize the on-off behavior of PPIs during infection with herpes simplex virus 1 (HSV-1), a virus with an ancient history of coevolution with hosts. Advancing the TPCA analysis to infer associations de novo, we build a time-resolved portrait of thousands of host-host, virus-host, and virus-virus PPIs. We demonstrate that, early in infection, the DNA sensor IFI16 recruits the active DNA damage response kinase, DNA-dependent protein kinase (DNA-PK), to incoming viral DNA at the nuclear periphery. We establish IFI16 T149 as a substrate of DNA-PK upon viral infection or DNA damage. This phosphorylation promotes IFI16-driven cytokine responses. Together, we characterize the global dynamics of PPIs during HSV-1 infection, uncovering the co-regulation of IFI16 and DNA-PK functions as a missing link in immunity to herpesvirus infection.</p>

DOI10.1126/sciadv.abg6680
Alternate JournalSci Adv
PubMed ID34144993
PubMed Central IDPMC8213230
Grant ListR01 GM114141 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States