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

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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. Significance Infection of pathogenic microbes induces the body to produce cytokines, which are mediators of inflammation. IL-1β plays central roles in the initiation of inflammatory and immune responses. In this study, we identified MARCH3 protein, which negatively regulates IL-1β–triggered signaling and inflammatory response by mediating K48-linked polyubiquitination of IL-1RI at lysine 409 and its lysosomal degradation. Our findings reveal a mechanism for how IL-1β–triggered inflammatory response is attenuated by down-regulation of IL-1β receptor.
Funding Information
  • State Key R&D Program of China (2017YFA0505800)
  • State Key R&D Program of China (2016YFA0502102)
  • National Natural Science Foundation of China (31630045)
  • National Natural Science Foundation of China (31521091)
  • National Natural Science Foundation of China (31671465)
  • National Natural Science Foundation of China (31830024)
  • National Natural Science Foundation of China (318001188)

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