title: Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO.
abstract: Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding-association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.
authors.affiliation: 1] National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China. [2] National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China. [3].
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China. [2].
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Han
authors.affiliation: 1] Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China. [2].
authors.forename: Bin
authors.initials: B
authors.lastname: Xie
authors.affiliation: 1] Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai, China. [2].
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Shuxun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xia
authors.affiliation: National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Song
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Deng
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.affiliation: 1] National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China. [2] National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China. [3] Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015551:Autoimmunity; D003713:Dendritic Cells / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology; D054875:Ubiquitination; D000093242:Interleukin-6 Inhibitors
chemical_list: D051017:Apoptosis Regulatory Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine; D016328:NF-kappa B; D051193:Toll-Like Receptors; D000093242:Interleukin-6 Inhibitors; C514981:NEMO protein, mouse; C582250:RHBDD3 protein, mouse