TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity

J Virol. 2013 Jan;87(1):257-72. doi: 10.1128/JVI.01804-12. Epub 2012 Oct 17.


Members of the tripartite interaction motif (TRIM) family of E3 ligases are emerging as critical regulators of innate immunity. To identify new regulators, we carried out a screen of 43 human TRIM proteins for the ability to activate NF-κB, AP-1, and interferon, hallmarks of many innate immune signaling pathways. We identified 16 TRIM proteins that induced NF-κB and/or AP-1. We found that one of these, TRIM62, functions in the TRIF branch of the TLR4 signaling pathway. Knockdown of TRIM62 in primary macrophages led to a defect in TRIF-mediated late NF-κB, AP-1, and interferon production after lipopolysaccharide challenge. We also discovered a role for TRIM15 in the RIG-I-mediated interferon pathway upstream of MAVS. Knockdown of TRIM15 limited virus/RIG-I ligand-induced interferon production and enhanced vesicular stomatitis virus replication. In addition, most TRIM proteins previously identified to inhibit murine leukemia virus (MLV) demonstrated an ability to induce NF-κB/AP-1. Interfering with the NF-κB and AP-1 signaling induced by the antiretroviral TRIM1 and TRIM62 proteins rescued MLV release. In contrast, human immunodeficiency virus type 1 (HIV-1) gene expression was increased by TRIM proteins that induce NF-κB. HIV-1 resistance to inflammatory TRIM proteins mapped to the NF-κB sites in the HIV-1 long terminal repeat (LTR) U3 and could be transferred to MLV. Thus, our work identifies new TRIM proteins involved in innate immune signaling and reinforces the striking ability of HIV-1 to exploit innate immune signaling for the purpose of viral replication.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Gene Knockdown Techniques
  • HIV-1 / immunology*
  • Humans
  • Immunity, Innate*
  • Interferons / metabolism
  • Leukemia Virus, Murine / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • NF-kappa B / metabolism
  • Signal Transduction*
  • Transcription Factor AP-1 / metabolism
  • Vesiculovirus / immunology*


  • Adaptor Proteins, Signal Transducing
  • Membrane Proteins
  • NF-kappa B
  • TRAT1 protein, human
  • Transcription Factor AP-1
  • Interferons