期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 49, 页码 12483-12488出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1806217115
关键词
MARCH3; IL-1; Listeria monocytogenes; polyubiquitination; inflammation
资金
- State Key R&D Program of China [2017YFA0505800, 2016YFA0502102]
- National Natural Science Foundation of China [31630045, 31521091, 31671465, 31830024, 318001188]
The proinflammatory cytokine IL-1 beta plays critical roles in inflammatory and autoimmune diseases. IL-1 beta 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-1 beta-triggered signaling. Overexpression of MARCH3 inhibited IL-1 beta-triggered activation of NF-kappa B 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-1 beta 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-1 beta 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-1 beta-triggered inflammatory response.
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