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Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):12483-12488. doi: 10.1073/pnas.1806217115. Epub 2018 Nov 15.

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

Author information

1
Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
2
College of Life Sciences, Wuhan University, 430072, Wuhan, China.
3
Wuhan Institute of Virology, State Key Laboratory of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.
4
Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China; shuh@whu.edu.cn.

Abstract

The proinflammatory cytokine IL-1β plays critical roles in inflammatory and autoimmune diseases. IL-1β 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-1β-triggered signaling. Overexpression of MARCH3 inhibited IL-1β-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-1β 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-1β 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-1β-triggered inflammatory response.

KEYWORDS:

IL-1; Listeria monocytogenes; MARCH3; inflammation; polyubiquitination

PMID:
30442668
PMCID:
PMC6298087
[Available on 2019-06-04]
DOI:
10.1073/pnas.1806217115

Conflict of interest statement

The authors declare no conflict of interest.

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