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MARCH3 attenuates IL-1ß-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI.

Lin, Heng; Gao, Deng; Hu, Ming-Ming; Zhang, Man; Wu, Xiao-Xia; Feng, Lu; Xu, Wen-Hua; Yang, Qing; Zhong, Xuan; Wei, Jin; Xu, Zhi-Sheng; Zhang, Hong-Xia; Song, Ze-Min; Zhou, Qian; Ye, Wen; Liu, Ying; Li, Shu; Shu, Hong-Bing.
Proc Natl Acad Sci U S A; 115(49): 12483-12488, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30442668
The proinflammatory cytokine IL-1ß plays critical roles in inflammatory and autoimmune diseases. IL-1ß signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1ß-triggered signaling. Overexpression of MARCH3 inhibited IL-1ß-triggered activation of NF-κB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1ß injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1ß stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3-mediated IL-1RI degradation is an important mechanism for attenuating IL-1ß-triggered inflammatory response.
Selo DaSilva