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

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 iden...

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Autores principales: Duan, Jie-Lin, He, Hui-Qian, Yu, Yao, Liu, Tao, Ma, Shu-Jun, Li, Fan, Jiang, Yan-Shan, Lin, Xin, Li, De-Dong, Lv, Quan-Zhen, Ma, Hui-Hui, Jia, Xin-Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104877/
https://www.ncbi.nlm.nih.gov/pubmed/33962939
http://dx.doi.org/10.1126/sciadv.abe5171
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author Duan, Jie-Lin
He, Hui-Qian
Yu, Yao
Liu, Tao
Ma, Shu-Jun
Li, Fan
Jiang, Yan-Shan
Lin, Xin
Li, De-Dong
Lv, Quan-Zhen
Ma, Hui-Hui
Jia, Xin-Ming
author_facet Duan, Jie-Lin
He, Hui-Qian
Yu, Yao
Liu, Tao
Ma, Shu-Jun
Li, Fan
Jiang, Yan-Shan
Lin, Xin
Li, De-Dong
Lv, Quan-Zhen
Ma, Hui-Hui
Jia, Xin-Ming
author_sort Duan, Jie-Lin
collection PubMed
description 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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spelling pubmed-81048772021-05-17 E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation Duan, Jie-Lin He, Hui-Qian Yu, Yao Liu, Tao Ma, Shu-Jun Li, Fan Jiang, Yan-Shan Lin, Xin Li, De-Dong Lv, Quan-Zhen Ma, Hui-Hui Jia, Xin-Ming Sci Adv Research Articles 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. American Association for the Advancement of Science 2021-05-07 /pmc/articles/PMC8104877/ /pubmed/33962939 http://dx.doi.org/10.1126/sciadv.abe5171 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Duan, Jie-Lin
He, Hui-Qian
Yu, Yao
Liu, Tao
Ma, Shu-Jun
Li, Fan
Jiang, Yan-Shan
Lin, Xin
Li, De-Dong
Lv, Quan-Zhen
Ma, Hui-Hui
Jia, Xin-Ming
E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
title E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
title_full E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
title_fullStr E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
title_full_unstemmed E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
title_short E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation
title_sort e3 ligase c-cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical nf-κb activation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104877/
https://www.ncbi.nlm.nih.gov/pubmed/33962939
http://dx.doi.org/10.1126/sciadv.abe5171
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