Title

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

UMMS Affiliation

Program in Molecular Medicine; Center for AIDS Research

Publication Date

1-2013

Document Type

Article

Disciplines

Biochemistry | Immunity | Immunology of Infectious Disease | Molecular Biology | Virology | Viruses

Abstract

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-kappaB, AP-1, and interferon, hallmarks of many innate immune signaling pathways. We identified 16 TRIM proteins that induced NF-kappaB 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-kappaB, 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-kappaB/AP-1. Interfering with the NF-kappaB 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-kappaB. HIV-1 resistance to inflammatory TRIM proteins mapped to the NF-kappaB 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.

DOI of Published Version

10.1128/JVI.01804-12

Source

J Virol. 2013 Jan;87(1):257-72. doi: 10.1128/JVI.01804-12. Epub 2012 Oct 17. Link to article on publisher's site

Journal/Book/Conference Title

Journal of virology

Related Resources

Link to Article in PubMed

PubMed ID

23077300

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