TRIM14 Is a Key Regulator of the Type I IFN Response during <i>Mycobacterium tuberculosis</i> Infection

Abstract

Tripartite motif-containing proteins (TRIMs) play a variety of recently described roles in innate immunity. Although many TRIMs regulate type I IFN expression following cytosolic nucleic acid sensing of viruses, their contribution to innate immune signaling and gene expression during bacterial infection remains largely unknown. Because <i>Mycobacterium tuberculosis</i> is an activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to <i>M. tuberculosis</i> In this study, we demonstrate that TRIM14, a noncanonical TRIM that lacks an E3 ubiquitin ligase RING domain, is a critical negative regulator of the type I IFN response in <i>Mus musculus</i> macrophages. We show that TRIM14 interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce IFN stimulated gene (ISG) expression following <i>M. tuberculosis</i> infection, cytosolic nucleic acid transfection, and IFN-β treatment. Consistent with a defect in resolution of the type I IFN response, <i>Trim14</i> knockout macrophages have more phospho-Ser754 STAT3 relative to phospho-Ser727 and fail to upregulate the STAT3 target <i>Socs3</i>, which is required to turn off IFNAR signaling. These data support a model whereby TRIM14 acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 at Ser727 and resolve ISG expression. Remarkably, <i>Trim14</i> knockout macrophages hyperinduce expression of antimicrobial genes like <i>Nos2</i> and are significantly better than control cells at limiting <i>M. tuberculosis</i> replication. Collectively, these data reveal an unappreciated role for TRIM14 in resolving type I IFN responses and controlling <i>M. tuberculosis</i> infection.