Title | Interactome and Proteome Dynamics Uncover Immune Modulatory Associations of the Pathogen Sensing Factor cGAS. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Lum, KK, Song, B, Federspiel, JD, Diner, BA, Howard, T, Cristea, IM |
Journal | Cell Syst |
Volume | 7 |
Issue | 6 |
Pagination | 627-642.e6 |
Date Published | 2018 Dec 26 |
ISSN | 2405-4712 |
Keywords | Apoptosis, Cell Line, Cytokines, Herpes Simplex, Herpesvirus 1, Human, Humans, Immunity, Innate, Interferons, Nucleotidyltransferases, Protein Interaction Maps, Proteome |
Abstract | <p>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.</p> |
DOI | 10.1016/j.cels.2018.10.010 |
Alternate Journal | Cell Syst |
PubMed ID | 30471916 |
PubMed Central ID | PMC6310102 |
Grant List | F31 GM120936 / GM / NIGMS NIH HHS / United States R01 GM114141 / GM / NIGMS NIH HHS / United States T32 GM007388 / GM / NIGMS NIH HHS / United States |