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E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
- Source :
- Science Advances
- Publication Year :
- 2021
- Publisher :
- American Association for the Advancement of Science, 2021.
-
Abstract
- c-Cbl suppresses RelB activation to facilitate protective benefits of commensal fungi and maintain intestinal homeostasis.<br />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.
- Subjects :
- Ubiquitin-Protein Ligases
Immunology
03 medical and health sciences
Mice
0302 clinical medicine
Ubiquitin
Transcription (biology)
hemic and lymphatic diseases
medicine
Animals
Proto-Oncogene Proteins c-cbl
Colitis
Research Articles
030304 developmental biology
Inflammation
0303 health sciences
Multidisciplinary
biology
Chemistry
RELB
fungi
Fungi
NF-kappa B
SciAdv r-articles
Dendritic cell
medicine.disease
Ubiquitin ligase
Cell biology
Interleukin 10
030220 oncology & carcinogenesis
biology.protein
Tyrosine kinase
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 23752548
- Volume :
- 7
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Science Advances
- Accession number :
- edsair.doi.dedup.....8bc106166540138b29d7e67104af45fe