期刊
JOURNAL OF IMMUNOLOGY
卷 189, 期 11, 页码 5304-5313出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1201445
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资金
- Ministry of Science and Technology of China [2012CB519003, 2011CB504802, 2011CB504705]
- Chinese Academy of Sciences [KSCX2-YW-R-198, KSCX2-EW-J-6]
- Innovative Research Group of the National Natural Science Foundation of China [81021003]
Ndfip1 functions as both a recruiter and an activator of multiple HECT domain E3 ubiquitin ligases of the Nedd4 family. In this study, we demonstrate that Ndfip1 is involved in the ubiquitin-mediated degradation of mitochondrial antiviral signaling (MAVS), which is a key adaptor protein in RIG-I-like receptor-mediated immune signaling. We found that overexpression of Ndfip1 severely impaired MAVS and Sendai virus-mediated activation of IFN-stimulated response element, NF-kappa B, IFN-beta promoter, and polyinosinic-polycytidylic acid or influenza virus RNA-stimulated IRF-3 phosphorylation, as well as the transcription of IFN-beta. This functional interaction was confirmed by knockdown of Ndfip1, which facilitated MAVS-mediated downstream signaling and elevated MAVS protein levels. Further analysis indicated that Ndfip1 enhances both self-ubiquitination of HECT domain-containing E3 ubiquitin ligase Smurf1 and its interaction with MAVS, and eventually promotes MAVS degradation. In addition, the activation of IFN-beta by MAVS, influenza virus RNA, polyinosinic-polycytidylic acid, and Sendai virus was enhanced in Ndfip1 knockdown cells. These results reveal that Ndfip1 is a potent inhibitor of MAVS-mediated antiviral response. The Journal of Immunology, 2012, 189: 5304-5313.
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