E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity

Le Le Zhu, Tian Ming Luo, Xia Xu, Ya Hui Guo, Xue Qiang Zhao, Ting Ting Wang, Bing Tang, Yuan Ying Jiang, Jin Fu Xu, Xin Lin, Xin Ming Jia

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Activation of various C-type lectin receptors (CLRs) initiates potent proinflammatory responses against various microbial infections. However, how activated CLRs are negatively regulated remains unknown. In this study, we report that activation of CLRs Dectin-2 and Dectin-3 by fungi infections triggers them for ubiquitination and degradation in a Syk-dependent manner. Furthermore, we found that E3 ubiquitin ligase Casitas B-lineage lymphoma protein b (Cbl-b) mediates the ubiquitination of these activated CLRs through associating with each other via adapter protein FcR-γ and tyrosine kinase Syk, and then the ubiquitinated CLRs are sorted into lysosomes for degradation by an endosomal sorting complex required for transport (ESC RT) system. Therefore, the deficiency of either Cbl-b or ESC RT subunits significantly decreases the degradation of activated CLRs, thereby resulting in the higher expression of proinflammatory cytokines and inflammation. Consistently, Cbl-b-deficient mice are more resistant to fungi infections compared with wild-type controls. Together, our study indicates that Cbl-b negatively regulates CLR-mediated antifungal innate immunity, which provides molecular insight for designing antifungal therapeutic agents.

Original languageEnglish (US)
Pages (from-to)1555-1570
Number of pages16
JournalJournal of Experimental Medicine
Volume213
Issue number8
DOIs
StatePublished - Jul 25 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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