Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders

Dan Lu; Jia Song; Yizhe Sun; Fang Qi; Liang Liu; Yan Jin; Michael A McNutt; Yuxin Yin

doi:10.1016/j.jaut.2018.07.019

Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders

J Autoimmun. 2018 Nov:94:156-165. doi: 10.1016/j.jaut.2018.07.019. Epub 2018 Aug 10.

Authors

Dan Lu¹, Jia Song², Yizhe Sun², Fang Qi², Liang Liu¹, Yan Jin¹, Michael A McNutt¹, Yuxin Yin³

Affiliations

¹ Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, 100191, PR China.
² Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, 100191, PR China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
³ Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, 100191, PR China; Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, PR China; Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, 100191, PR China. Electronic address: yinyuxin@hsc.pku.edu.cn.

PMID: 30100102
DOI: 10.1016/j.jaut.2018.07.019

Abstract

Dysregulation of innate immunity accompanied by excessive interferon production contributes to autoimmune disease. However, the mechanism by which the immune response is modulated in autoimmune disorders is largely unknown. Here we identified loss-of-function mutations of OTUD1 associated with multiple autoimmune diseases. Under inflammatory conditions, inducible OTUD1 acts as an immune checkpoint and blocks RIG-I-like receptors signaling. As a deubiquitinase, OTUD1 directly interacts with transcription factor IRF3 and removes the K63-linked poly-ubiquitin chains on IRF3 Lysine 98, which inhibits IRF3 nuclear translocation and transcriptional activity. In contrast, OTUD1 mutants impair its suppressive effects on IRF3 via attenuating the OTUD1 deubiquinase activity or its association with IRF3. Moreover, we found FOXO3 signaling is required for OTUD1 induction upon antigenic stimulation. Our data demonstrate that OTUD1 is involved in maintaining immune homeostasis and loss-of-function mutations of OTUD1 enhance the immune response and are associated with autoimmunity.

Keywords: Autoimmunity; Deubiquitinase; IRF3; Loss-of-function mutation; OTUD1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amino Acid Sequence
Arthritis, Rheumatoid / genetics*
Arthritis, Rheumatoid / immunology
Arthritis, Rheumatoid / pathology
Case-Control Studies
Cell Line, Tumor
Colitis, Ulcerative / genetics*
Colitis, Ulcerative / immunology
Colitis, Ulcerative / pathology
DEAD Box Protein 58 / genetics
DEAD Box Protein 58 / immunology
Female
Forkhead Box Protein O3 / genetics
Forkhead Box Protein O3 / immunology
Gene Expression Regulation
HEK293 Cells
Hashimoto Disease / genetics*
Hashimoto Disease / immunology
Hashimoto Disease / pathology
Homeostasis / immunology
Humans
Interferon Regulatory Factor-3 / genetics
Interferon Regulatory Factor-3 / immunology
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / immunology
Lupus Erythematosus, Systemic / pathology
Lymphocytes / immunology*
Lymphocytes / pathology
Male
Mutation
Protein Transport
Receptors, Immunologic
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction
Ubiquitin-Specific Proteases / genetics*
Ubiquitin-Specific Proteases / immunology

Substances

FOXO3 protein, human
Forkhead Box Protein O3
IRF3 protein, human
Interferon Regulatory Factor-3
Receptors, Immunologic
OTUD1 protein, human
Ubiquitin-Specific Proteases
RIGI protein, human
DEAD Box Protein 58