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
2013-1
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
PubMed ID
23077300
Repository Citation
Uchil, Pradeep D.; Hinz, Angelika; Siegel, Steven; Coenen-Stass, Anna; Pertel, Thomas; Luban, Jeremy; and Mothes, Walther, "TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity" (2013). Program in Molecular Medicine Publications and Presentations. 82.
https://escholarship.umassmed.edu/pmm_pp/82