Title | Systematic profiling of protein complex dynamics reveals DNA-PK phosphorylation of IFI16 en route to herpesvirus immunity. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Justice, JL, Kennedy, MA, Hutton, JE, Liu, D, Song, B, Phelan, B, Cristea, IM |
Journal | Sci Adv |
Volume | 7 |
Issue | 25 |
Date Published | 2021 06 |
ISSN | 2375-2548 |
Keywords | Herpes 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> |
DOI | 10.1126/sciadv.abg6680 |
Alternate Journal | Sci Adv |
PubMed ID | 34144993 |
PubMed Central ID | PMC8213230 |
Grant List | R01 GM114141 / GM / NIGMS NIH HHS / United States T32 GM007388 / GM / NIGMS NIH HHS / United States |