Reciprocal regulation of IL-33 receptor–mediated inflammatory response and pulmonary fibrosis by TRAF6 and USP38

Significance IL-33R mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases. In this study, we identified USP38, which negatively regulates IL-33-triggered signaling by mediating K27-linked deubiquitination of IL-33R at K511 and its autophagic degradation. USP38 deficiency aggravates IL-33–induced lung inflammatory response and bleomycin-induced pulmonary fibrosis. We further show that the E3 ubiquitin ligase TRAF6 catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33–mediated signaling. Our findings reveal an important mechanism regarding how IL-33R is precisely regulated to ensure its inactivation in rest cells and proper activation following IL-33 stimulation.