E3 Ligase c-Cbl Regulates Intestinal Inflammation Through Suppressing Fungi-Induced Noncanonical NF-κΒ Activation

Abstract

Accumulating evidence reveals a pivotal role of intestinal fungi in modulating host immune homeostasis. However, the mechanisms for regulating immunity to commensal gut fungi remain unknown. Here, we show that dendritic cell (DC)-specific deficiency of casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase, confers mice susceptible to dextran sodium sulfate-induced colitis. Moreover, c-Cbl functions as a signal mediator downstream of α-mannan recognition receptor Dectin-2 and Dectin-3 by mediating the ubiquitination and degradation of non-canonical NF-κB subunit RelB. Thus, DC-specific deficiency of c-Cbl facilitates fungi-derived α-mannan-induced activation of RelB, which suppresses p65-mediated transcription of an anti-inflammatory cytokine gene il10. Consequently, suppressing fungal growth or inhibition of RelB activation in vivo significantly attenuates colitis in c-Cblf/fCD11cCre/+ mice whereas treatment of DPH, agonist of c-Abl, could synergistically increase the fungi-induced activation of c-Cbl to restrict colitis. These data unravel a role of c-Cbl/RelB axis in regulating intestinal inflammation for sustaining intestinal homeostasis, and a potential clinical utility of DPH for colitis treatment.