Keck School of Medicine Events

TRIMmunity: Regulators of Pathogen Restriction and Immune Responses

KSOM Research Seminar Series
December 2013
Monday, December 16, 2013
12:00 PM - 1:00 PM
Aresty Auditorium, NRT LG

Adolfo Garcia-Sastre, PhD, Professor, Department of Microbiology, Mount Sinai School of Medicine
Abstract: Pathogen sensing results in multiple signaling cascades that control the induction of innate immune responses and the secretion of essential antimicrobial cytokines. These signaling processes are highly regulated, and multiple cellular proteins have been found to both positively and negatively regulate the induction of innate immunity. We conducted a focused screen to analyze the impact of TRIM proteins, a family of E3-ubiquitin ligases with more than 70 members in mammalian species, in controlling the transcriptional induction of promoters involved in innate immune responses. Surprisingly, we found that at least half of the TRIM members are positive regulators of the interferon and NF-kB responsive promoters involved in antimicrobial innate immunity. Specific TRIM proteins appear to regulate these responses at different points during innate immune signaling. We have conducted mechanistic studies to understand the ability of TRIM6, for which no function was previously ascribed, in promoting antimicrobial responses. We found that TRIM6, together with the E2 ligase UbE2K, participates in the synthesis of K48-linked polyubiquitin chains, which activate the kinase IKKe for subsequent STAT1 phosphorylation during IFN signaling. As a result, TRIM6 is required for the induction of IKKe-dependent IFN stimulated genes with antiviral activity. Our work defines a previously unrecognized activating role of K48-linked polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and the antiviral response.

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