期刊
CELLULAR SIGNALLING
卷 91, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2021.110210
关键词
TNF-?; NF-?B; TRIM15; TRIM8; Ubiquitination; Functional antagonism
类别
资金
- Department of Biotechnology, Govt. of India [BT/PR20692/BRB/10/1538/2016]
- Maharaja Sayajirao University of Baroda [SR/FST/LS-11/2017/87]
- University Grant Commission (UGC)
- Council of Scientific & Industrial Research (CSIR)
- Indian Council of Medical Research (ICMR), Govt. of India
- Department of Science and Technology (DST), Govt. of India
The study identified TRIM proteins as potential feedback regulators of the TNF-alpha-induced NF-kappa B pathway. TRIM15 was found to be a late response gene induced by TNF-alpha and inhibits the NF-kappa B pathway in human cell lines. It promotes turnover of K63-linked ubiquitin chains and inhibits the activity of TAK1 and TRIM8, thus regulating the proinflammatory NF-kappa B pathway.
Ubiquitin E3-ligases are recruited at different steps of TNF-alpha-induced NF-kappa B activation; however, their role in temporal regulation of the pathway remains elusive. The study systematically identified TRIMs as potential feedback regulators of the TNF-alpha-induced NF-kappa B pathway. We further observed that TRIM15 is late response TNF-alpha-induced gene and inhibits the TNF-alpha-induced NF-kappa B pathway in several human cell lines. TRIM15 promotes turnover of K63-linked ubiquitin chains in a PRY/SPRY domain-dependent manner. TRIM15 interacts with TAK1 and inhibits its K63-linked ubiquitination, thus NF-kappa B activity. Further, TRIM15 interacts with TRIM8 and inhibits cytosolic translocation to antagonize TRIM8 modualted NF-kappa B. TRIM8 and TRIM15 also show functionally inverse correlation in psoriasis condition. In conclusion, TRIM15 is TNF-alpha-induced late response gene and inhibits TNF-alpha induced NF-kappa B pathway hence a feedback modulator to keep the proinflammatory NF-kappa B pathway under control.
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