title: MyD88 NEDDylation negatively regulates MyD88-dependent NF-κB signaling through antagonizing its ubiquitination.
abstract: Myeloid differentiation factor 88 (MyD88) plays a central role in innate immunity response, however, how its activity is tightly regulated remains largely unknown. In this study, we identify MyD88 as a novel substrate of NEDD8, and demonstrate that MyD88 NEDDylation antagonizes its ubiquitination. Interestingly, in response to the stimulation of IL-1β, MyD88 NEDDylation is downregulated while its ubiquitination is upregulated. We also show that deNEDDylase NEDP1 serves as a regulator of this process. Furthermore, we demonstrate that NEDD8 negatively regulates the dimerization of MyD88 and suppresses MyD88-dependent NF-κB signaling. Taken together, this study reveals that NEDDylation of MyD88 regulates NF-κB activity through antagonizing its ubiquitination, suggesting a novel mechanism of modulating NF-κB signaling pathway.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Fangxue
authors.initials: F
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Junhong
authors.initials: J
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: xiaofengz@pku.edu.cn.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
mesh_terms: D010450:Endopeptidases / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000276:immunology*; D015398:Signal Transduction; D054875:Ubiquitination; D014452:Ubiquitins / Q000276:immunology*
chemical_list: D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D014452:Ubiquitins; D010450:Endopeptidases; C477008:SENP8 protein, human
keywords: IL-1β; MyD88 NEDDylation; NEDP1; NF-κB; Ubiquitination