Interactome and Proteome Dynamics Uncover Immune Modulatory Associations of the Pathogen Sensing Factor cGAS.

TitleInteractome and Proteome Dynamics Uncover Immune Modulatory Associations of the Pathogen Sensing Factor cGAS.
Publication TypeJournal Article
Year of Publication2018
AuthorsLum, KK, Song, B, Federspiel, JD, Diner, BA, Howard, T, Cristea, IM
JournalCell Syst
Volume7
Issue6
Pagination627-642.e6
Date Published2018 Dec 26
ISSN2405-4712
Abstract

Viral DNA sensing is an essential component of the mammalian innate immune response. Upon binding viral DNA, the cyclic-GMP-AMP synthase (cGAS) catalyzes the production of cyclic dinucleotides to induce type I interferons. However, little is known about how cGAS is homeostatically maintained or regulated upon infection. Here, we define cytoplasmic cGAS interactions with cellular and viral proteins upon herpes simplex virus type 1 (HSV-1) infection in primary human fibroblasts. We compare several HSV-1 strains (wild-type, d109, d106) that induce cytokine responses and apoptosis and place cGAS interactions in the context of temporal proteome alterations using isobaric-labeling mass spectrometry. Follow-up analyses establish a functional interaction between cGAS and 2'-5'-oligoadenylate synthase-like protein OASL. The OAS-like domain interacts with the cGAS Mab21 domain, while the OASL ubiquitin-like domain further inhibits cGAS-mediated interferon response. Our findings explain how cGAS may be inactively maintained in cellular homeostasis, with OASL functioning as a negative feedback loop for cytokine induction.

DOI10.1016/j.cels.2018.10.010
Alternate JournalCell Syst
PubMed ID30471916
PubMed Central IDPMC6310102
Grant ListF31 GM120936 / GM / NIGMS NIH HHS / United States
R01 GM114141 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States