title: E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity.
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 (ESCRT) system. Therefore, the deficiency of either Cbl-b or ESCRT 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.
authors.affiliation: Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
authors.forename: Le-Le
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Tian-Ming
authors.identifier: 0000-0002-6263-7854
authors.initials: TM
authors.lastname: Luo
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Ya-Hui
authors.identifier: 0000-0003-1587-4619
authors.initials: YH
authors.lastname: Guo
authors.affiliation: Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Xue-Qiang
authors.initials: XQ
authors.lastname: Zhao
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Department of Burns, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yuan-Ying
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
authors.forename: Jin-Fu
authors.identifier: 0000-0002-8039-8973
authors.initials: JF
authors.lastname: Xu
authors.affiliation: Institute for Immunology, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 jiaxm@tongji.edu.cn xllin@mdanderson.org.
authors.forename: Xin
authors.identifier: 0000-0003-0956-3654
authors.initials: X
authors.lastname: Lin
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China jiaxm@tongji.edu.cn xllin@mdanderson.org.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Jia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D000072377:Syk Kinase / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; C584161:Clec4d protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; C445340:dectin-2, mouse; D050721:Proto-Oncogene Proteins c-cbl; D000072377:Syk Kinase; C000606897:Syk protein, mouse