期刊
JOURNAL OF VIROLOGY
卷 87, 期 1, 页码 257-272出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01804-12
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资金
- National Institutes of Health [R21-AI087467, R01-CA098727]
- NATIONAL CANCER INSTITUTE [R01CA098727] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI087467] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [DP1DA034990] Funding Source: NIH RePORTER
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-kappa B, AP-1, and interferon, hallmarks of many innate immune signaling pathways. We identified 16 TRIM proteins that induced NF-kappa B 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-kappa B, 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-kappa B/AP-1. Interfering with the NF-kappa B 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-kappa B. HIV-1 resistance to inflammatory TRIM proteins mapped to the NF-kappa B 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.
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