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E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2

文献类型：期刊论文

作者Li, Hui2,3,4,5; Wang, Ning2,3; Jiang, Yu2,3; Wang, Haofei2,3; Xin, Zengfeng2,3; An, Huazhang6,7; Pan, Hao8; Ma, Wangqian9; Zhang, Ting1; Wang, Xiaojian2,3
刊名EMBO REPORTS
出版日期2022-09-26
ISSN号1469-221X
关键词IL-17R signaling inflammation MEKK2 NEDD4L ubiquitination
DOI10.15252/embr.202254603
通讯作者Zhang, Ting(zezht@zju.edu.cn) ; Wang, Xiaojian(wangxiaojian@cad.zju.edu.cn) ; Lin, Wenlong(lwl210@foxmail.com)
英文摘要Aberrant activation of inflammation signaling triggered by tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-17 (IL-17) is associated with immunopathology. Here, we identify neural precursor cells expressed developmentally down-regulated gene 4-like (NEDD4L), a HECT type E3 ligase, as a common negative regulator of signaling induced by TNF-alpha, IL-1, and IL-17. NEDD4L modulates the degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) via constitutively and directly binding to MEKK2 and promotes its poly-ubiquitination. In interleukin-17 receptor (IL-17R) signaling, Nedd4l knockdown or deficiency enhances IL-17-induced p38 and NF-kappa B activation and the production of proinflammatory cytokines and chemokines in a MEKK2-dependent manner. We further show that IL-17-induced MEKK2 Ser520 phosphorylation is required not only for downstream p38 and NF-kappa B activation but also for NEDD4L-mediated MEKK2 degradation and the subsequent shutdown of IL-17R signaling. Importantly, Nedd4l-deficient mice show increased susceptibility to IL-17-induced inflammation and aggravated symptoms of experimental autoimmune encephalomyelitis (EAE) in IL-17R signaling-dependent manner. These data suggest that NEDD4L acts as an inhibitor of IL-17R signaling, which ameliorates the pathogenesis of IL-17-mediated autoimmune diseases.
WOS关键词EPITHELIAL NA+ CHANNEL ; N-TERMINAL KINASE ; KAPPA-B ; GENE-EXPRESSION ; ACTIVATION ; RECEPTOR ; ALPHA ; TNF ; PHOSPHORYLATION ; MECHANISMS
资助项目National Key Basic Research Program of China[2014CB542101] ; National Key Basic Research Program of China[2013CB531606] ; National Natural Science Foundation of China[82071774] ; National Natural Science Foundation of China[31770932] ; National Natural Science Foundation of China[31970899] ; National Natural Science Foundation of China[81373153] ; National Natural Science Foundation of China[81571550] ; Natural Science Foundation of Zhejiang Province[LZ22H100001] ; Natural Science Foundation of Zhejiang Province[LR13C080001] ; Natural Science Foundation of Zhejiang Province[LY19H160048] ; Natural Science Foundation of Zhejiang Province[LY20H050006] ; Natural Science Foundation of Zhejiang Province[LY15H160006] ; Shanghai Key Laboratory of Cell Engineering[14DZ2272300] ; Shanghai Leading Academic Discipline Project[B905]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
出版者WILEY
WOS记录号WOS:000859155800001
资助机构National Key Basic Research Program of China ; National Natural Science Foundation of China ; Natural Science Foundation of Zhejiang Province ; Shanghai Key Laboratory of Cell Engineering ; Shanghai Leading Academic Discipline Project
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/129085]  
专题中国科学院合肥物质科学研究院
通讯作者Zhang, Ting; Wang, Xiaojian; Lin, Wenlong
作者单位1.Zhejiang Univ, Affiliated Hosp 2, Dept Radiat Oncol, Sch Med, Hangzhou, Peoples R China
2.Zhejiang Univ, Sch Med, Inst Immunol, Affiliated Hosp 2, Hangzhou, Zhejiang, Peoples R China
3.Zhejiang Univ, Sch Med, Dept Orthoped Surg, Affiliated Hosp 2, Hangzhou, Zhejiang, Peoples R China
4.Univ Chinese Acad Sci, Canc Hosp, Dept Med Oncol, Zhejiang Canc Hosp, Hangzhou, Peoples R China
5.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Hangzhou, Peoples R China
6.Shandong First Med Univ, Affiliated Hosp 1, Shandong Prov Key Lab Rheumat Dis & Translat Med, Jinan, Peoples R China
7.Shandong Prov Qianfoshan Hosp, Jinan, Peoples R China
8.Zhejiang Univ, Affiliated Hosp 1, Coll Med, Dept Urol, Hangzhou, Peoples R China
9.Zhejiang Univ, Affiliated Hosp 2, Dept Gastroenterol, Sch Med, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Li, Hui,Wang, Ning,Jiang, Yu,et al. E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2[J]. EMBO REPORTS,2022.
APA Li, Hui.,Wang, Ning.,Jiang, Yu.,Wang, Haofei.,Xin, Zengfeng.,...&Lin, Wenlong.(2022).E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2.EMBO REPORTS.
MLA Li, Hui,et al."E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2".EMBO REPORTS (2022).

入库方式： OAI收割

来源：合肥物质科学研究院

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