USP38 Inhibits Type I Interferon Signaling by Editing TBK1 Ubiquitination through NLRP4 Signalosome.
TBK1 is a component of the type I interferon (IFN) signaling pathway, yet the mechanisms controlling its activity and degradation remain poorly understood. Here we report that USP38 negatively regulates type I IFN signaling by targeting the active form of TBK1 for degradation in vitro and in vivo. USP38 specifically cleaves K33-linked poly-ubiquitin chains from TBK1 at Lys670, and it allows for subsequent K48-linked ubiquitination at the same position mediated by DTX4 and TRIP. Knockdown or knockout of USP38 increases K33-linked ubiquitination, but it abrogates K48-linked ubiquitination and degradation of TBK1, thus enhancing type I IFN signaling. Our findings identify an essential role for USP38 in negatively regulating type I IFN signaling, and they provide insights into the mechanisms by which USP38 regulates TBK1 ubiquitination through the NLRP4 signalosome.
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
Meng
M
Lin
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Zhiyao
Z
Zhao
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Zhifen
Z
Yang
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Qingcai
Q
Meng
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, TX 77030, USA.
Peng
P
Tan
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Weihong
W
Xie
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Yunfei
Y
Qin
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA; Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, TX 77030, USA. Electronic address: rwang3@houstonmethodist.org.
Rong-Fu
RF
Wang
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: cuij5@mail.sysu.edu.cn.
Jun
J
Cui
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000276:immunology; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D025821:Polyubiquitin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination; D018116:Vesiculovirus / Q000254:growth & development / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D039642:Eukaryotic Initiation Factors; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D025821:Polyubiquitin; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D064570:Ubiquitin-Specific Proteases; C000622389:Nlrp4 protein, mouse; C576121:TRIP-1 protein, mouse; C000592059:Rnh1 protein, mouse; C498588:Tbk1 protein, mouse; C000622388:Usp38 protein, mouse
K33 ubiquitination; TBK1 degradation; TBK1 ubiquitination; USP38 deubiquitination; innate immune signaling; type I interferon response