Journal
JOURNAL OF IMMUNOLOGY
Volume 188, Issue 11, Pages 5311-5318Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1103506
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Funding
- National Natural Science Foundation of China [81172813, 31000407]
- Taishan Scholar Program of Shandong Province
- Shandong Provincial Nature Science Foundation for Distinguished Young Scholars [JQ201120]
- Independent Innovation Foundation of Shandong University [2009JQ001]
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Recognition of RNA virus through TLR and RIG-I-like receptor results in rapid expression of type I IFNs, which play an essential role in host antiviral responses. However, the mechanisms to terminate the production of type I IFNs are not well defined. In the current study, we identified a member of the tripartite motif (TRIM) family, TRIM38, as a negative regulator in TLR3/4- and RIG-I mediated IFN-beta signaling. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of IFN regulatory factor 3 and enhanced expression of IFN-beta, whereas overexpression of TRIM38 had opposite effects. Coimmunoprecipitation and colocalization experiments demonstrated that TRIM38 interacted with NF-kappa B activating kinase-associated protein 1 (NAP1), which is required for TLR-induced IFN regulatory factor 3 activation and IFN-beta production. As an E3 ligase, TRIM38 promoted K48-linked polyubiquitination and proteasomal degradation of NAP1. Thus, knockdown of TRIM38 expression resulted in higher protein level of NAP1 in primary macrophages. Consistent with the inhibitory roles in TLR3/4- and RIG-I-mediated IFN-beta signaling, knockdown of TRIM38 significantly inhibited the replication of vesicular stomatitis virus. Overexpression of TRIM38 resulted in enhanced replication of vesicular stomatitis virus. Therefore, our results demonstrate that TRIM38 is a negative regulator for TLR and RIG-I-mediated IFN-beta production by targeting NAP1 for ubiquitination and subsequent proteasome-mediated degradation. The Journal of Immunology, 2012, 188: 5311-5318.
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