title: NDR1 protein kinase promotes IL-17- and TNF-α-mediated inflammation by competitively binding TRAF3.
abstract: Interleukin 17 (IL-17) is an important inducer of tissue inflammation and is involved in numerous autoimmune diseases. However, how its signal transduction is regulated is not well understood. Here, we report that nuclear Dbf2-related kinase 1 (NDR1) functions as a positive regulator of IL-17 signal transduction and IL-17-induced inflammation. NDR1 deficiency or knockdown inhibits the IL-17-induced phosphorylation of p38, ERK1/2, and p65 and the expression of chemokines and cytokines, whereas the overexpression of NDR1 promotes IL-17-induced signaling independent of its kinase activity. Mechanistically, NDR1 interacts with TRAF3 and prevents its binding to IL-17R, which promotes the formation of an IL-17R-Act1-TRAF6 complex and downstream signaling. Consistent with this, IL-17-induced inflammation is significantly reduced inNDR1-deficient mice, and NDR1 deficiency significantly protects mice from MOG-induced experimental autoimmune encephalomyelitis (EAE) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis likely by its inhibition of IL-17-mediated signaling pathway. NDR1 expression is increased in the colons of ulcerative colitis (UC) patients. Taken together, these findings suggest that NDR1 is involved in the development of autoimmune diseases.
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Ma
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Lin
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Rahul
authors.initials: R
authors.lastname: Gautam
authors.affiliation: Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China wangxiaojian@cad.zju.edu.cn.
authors.forename: Xiaojian
authors.identifier: 0000-0001-8232-0558
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D018345:Mice, Knockout; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D020381:Interleukin-17; D048008:TNF Receptor-Associated Factor 3; D014409:Tumor Necrosis Factor-alpha; C552947:NDR1 protein kinase, mouse; D017346:Protein Serine-Threonine Kinases
keywords: IL‐17; NDR1; TRAF3; inflammation