title: Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88.
abstract: Myeloid differentiation factor 88 (MyD88) acts as a crucial adaptor molecule for Toll-like receptors (TLRs) and interleukin (IL)-1 receptor signaling. In contrast to the well-studied positive regulation of MyD88 signaling, how MyD88 signaling is negatively regulated still remains largely unknown. Here, we demonstrate for the first time to our knowledge that MyD88 protein undergoes lysine 63 (K63)-linked polyubiquitination, which is functionally critical for mediating TLR-MyD88-dependent signaling. Deubiquitinase CYLD negatively regulates MyD88-mediated signaling by directly interacting with MyD88 and deubiquitinating nontypeable Haemophilus influenzae (NTHi)-induced K63-linked polyubiquitination of MyD88 at lysine 231. Importantly, we further confirmed this finding in the lungs of mice in vivo by using MyD88(-/-)CYLD(-/-) mice. Understanding how CYLD deubiquitinates K63-linked polyubiquitination of MyD88 may not only bring insights into the negative regulation of TLR-MyD88-dependent signaling, but may also lead to the development of a previously unidentified therapeutic strategy for uncontrolled inflammation.
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303;
authors.forename: Byung-Cheol
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303;
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyata
authors.affiliation: Department of Microbiology, Ewha Womans University School of Medicine, Seoul 158-710, Korea.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303; jdli@gsu.edu.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000074749:Deubiquitinating Enzyme CYLD; D006193:Haemophilus influenzae / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D053594:Myeloid Differentiation Factor 88; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; C409984:CYLD protein, human; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases; D008239:Lysine
keywords: CYLD; MyD88; deubiquitinase; polyubiquitination