TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity.
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.
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, USA.
Pradeep D
PD
Uchil
Angelika
A
Hinz
Steven
S
Siegel
Anna
A
Coenen-Stass
Thomas
T
Pertel
Jeremy
J
Luban
Walther
W
Mothes
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism; D009052:Leukemia Virus, Murine / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D018116:Vesiculovirus / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D016328:NF-kappa B; C114030:TRAT1 protein, human; D018808:Transcription Factor AP-1; D007372:Interferons