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  2. E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation

E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation

  • Sci Adv. 2021 May 7;7(19):eabe5171. doi: 10.1126/sciadv.abe5171.
Jie-Lin Duan 1 Hui-Qian He 1 Yao Yu 1 Tao Liu 1 Shu-Jun Ma 2 Fan Li 1 Yan-Shan Jiang 1 Xin Lin 3 De-Dong Li 1 Quan-Zhen Lv 1 Hui-Hui Ma 1 Xin-Ming Jia 4
Affiliations

Affiliations

  • 1 Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China.
  • 2 Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • 3 Institute for Immunology, Tsinghua University School of Medicine, Tsinghua University-Peking University Jointed Center for Life Sciences, Beijing 100084, China.
  • 4 Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China [email protected].
Abstract

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 κB subunit RelB. Thus, c-Cbl deficiency in DCs promotes α-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.

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