| First Author | Duan JL | Year | 2021 |
| Journal | Sci Adv | Volume | 7 |
| Issue | 19 | PubMed ID | 33962939 |
| Mgi Jnum | J:319819 | Mgi Id | MGI:6811953 |
| Doi | 10.1126/sciadv.abe5171 | Citation | Duan JL, et al. (2021) E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-kappaB activation. Sci Adv 7(19) |
| abstractText | Intestinal fungi are critical for modulating host immune homeostasis and underlying mechanisms remain unclear. We show that dendritic cell (DC)-specific deficiency of casitas B-lineage lymphoma (c-Cbl) renders mice susceptible to dextran sodium sulfate (DSS)-induced colitis. Mechanistically, we identify that c-Cbl functions downstream of Dectin-2 and Dectin-3 to mediate the ubiquitination and degradation of noncanonical nuclear factor kappaB subunit RelB. Thus, c-Cbl deficiency in DCs promotes alpha-mannan-induced activation of RelB, which suppresses p65-mediated transcription of an anti-inflammatory cytokine gene, il10, thereby aggravating DSS-induced colitis. Moreover, suppressing fungal growth with fluconazole or inhibition of RelB activation in vivo attenuates colitis in mice with DC-specific deletion of c-Cbl. We also demonstrate an interaction between c-Cbl and c-Abl tyrosine kinase and find that treatment with DPH, a c-Abl agonist, synergistically increases fungi-induced c-Cbl activation to restrict colitis. Together, these findings unravel a previously unidentified fungi-induced c-Cbl/RelB axis that sustains intestinal homeostasis and protects against intestinal inflammation. |
