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

47 Pages Posted: 18 Feb 2021 Publication Status: Review Complete

See all articles by Jie-Lin Duan

Jie-Lin Duan

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

Hui-Qian He

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

Tao Liu

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

Shu-Jun Ma

Second Military Medical University - Department of Dermatology

Fan Li

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

Xin Lin

Tsinghua University - Institute for Immunology

De-Dong Li

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

Xin-Ming Jia

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

More...

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.

Keywords: Intestinal inflammation; c-Cbl; gut fungi; noncanonical NF-κB

Suggested Citation

Duan, Jie-Lin and He, Hui-Qian and Liu, Tao and Ma, Shu-Jun and Li, Fan and Lin, Xin and Li, De-Dong and Jia, Xin-Ming, E3 Ligase c-Cbl Regulates Intestinal Inflammation Through Suppressing Fungi-Induced Noncanonical NF-κΒ Activation. Available at SSRN: https://ssrn.com/abstract=3787901 or http://dx.doi.org/10.2139/ssrn.3787901
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jie-Lin Duan

Tongji University - Clinical Medicine Scientific and Technical Innovation Center ( email )

China

Hui-Qian He

Tongji University - Clinical Medicine Scientific and Technical Innovation Center ( email )

China

Tao Liu

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

China

Shu-Jun Ma

Second Military Medical University - Department of Dermatology ( email )

800 Xiangyin Rd
Yangpu Qu
China

Fan Li

Tongji University - Clinical Medicine Scientific and Technical Innovation Center

China

Xin Lin

Tsinghua University - Institute for Immunology

Beijing, 100084
China

De-Dong Li

Tongji University - Clinical Medicine Scientific and Technical Innovation Center ( email )

China

Xin-Ming Jia (Contact Author)

Tongji University - Clinical Medicine Scientific and Technical Innovation Center ( email )

China

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