Trim14 Is a Key Regulator of the Type I Interferon Response during Mycobacterium tuberculosis Infection

Abstract

TRIM (tripartite motif) family proteins are distinguished as important players in the innate immune response to infection. TRIM14 has been heavily implicated in anti-viral innate immune signaling through various protein-protein interactions. However, TRIM14’s role during bacterial infection remains unclear. Here, I demonstrate that TRIM14 is a crucial negative regulator of type I interferon and interferon stimulated gene (ISG) expression during infection with Mycobacterium tuberculosis, a potent activator of cytosolic DNA sensing pathways. My data shows that TRIM14 directly interacts with the DNA sensing kinase TBK1 and that loss of TRIM14 leads to dramatic hyper-induction of IFN and ISGs in response to cytosolic nucleic acid agonists, including M. tuberculosis. Consistent with this phenotype, I report that loss of TRIM14 promotes phosphorylation of STAT3 at S754, leading to downregulation of negative regulators of ISG expression including SOCS3. Furthermore, in investigating ways in which TRIM14 could be regulated we discovered an isoform of TRIM14 that is upregulated upon M. tuberculosis infection. In addition, TRIM14 is differentially ubiquitinated and phosphorylated upon bacterial infection. I propose here that TRIM14 manipulates the host innate immune response against different pathogens at several distinct regulatory steps. Ultimately, TRIM14 activity may prove to be a good therapeutic target as limiting its activity could promote clearance of Mycobacterium tuberculosis infection.