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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2021
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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. |
format | Online Article Text |
id | pubmed-8104877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
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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