TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection

J Immunol. 2020 Jul 1;205(1):153-167. doi: 10.4049/jimmunol.1901511. Epub 2020 May 13.

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 Mycobacterium tuberculosis is an activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to M. tuberculosis 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 Mus musculus macrophages. We show that TRIM14 interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce IFN stimulated gene (ISG) expression following M. tuberculosis infection, cytosolic nucleic acid transfection, and IFN-β treatment. Consistent with a defect in resolution of the type I IFN response, Trim14 knockout macrophages have more phospho-Ser754 STAT3 relative to phospho-Ser727 and fail to upregulate the STAT3 target Socs3, 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, Trim14 knockout macrophages hyperinduce expression of antimicrobial genes like Nos2 and are significantly better than control cells at limiting M. tuberculosis replication. Collectively, these data reveal an unappreciated role for TRIM14 in resolving type I IFN responses and controlling M. tuberculosis infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gene Expression Regulation / immunology
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Interferon Type I / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / isolation & purification
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mycobacterium tuberculosis / immunology*
  • Nitric Oxide Synthase Type II / metabolism
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / isolation & purification
  • Nucleotidyltransferases / metabolism
  • Phosphorylation / immunology
  • Primary Cell Culture
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / isolation & purification
  • Protein-Serine-Threonine Kinases / metabolism
  • RAW 264.7 Cells
  • Receptor, Interferon alpha-beta / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / immunology*
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / isolation & purification
  • Tripartite Motif Proteins / metabolism*
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology

Substances

  • Interferon Type I
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Sting1 protein, mouse
  • Trim14 protein, mouse
  • Tripartite Motif Proteins
  • Receptor, Interferon alpha-beta
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Nucleotidyltransferases
  • cGAS protein, human