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

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.