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

doi:10.15252/embr.202254603

	E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2
	Li, Hui 1,2,3,4; Wang, Ning 1,2; Jiang, Yu 1,2; Wang, Haofei 1,2; Xin, Zengfeng 1,2; An, Huazhang 5,6; Pan, Hao 8; Ma, Wangqian 9; Zhang, Ting 7; Wang, Xiaojian 1,2
刊名	EMBO REPORTS
	2022-09-26
关键词	IL-17R signaling inflammation MEKK2 NEDD4L ubiquitination
ISSN号	1469-221X
DOI	10.15252/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.
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关键词	EPITHELIAL NA+ CHANNEL ; N-TERMINAL KINASE ; KAPPA-B ; GENE-EXPRESSION ; ACTIVATION ; RECEPTOR ; ALPHA ; TNF ; PHOSPHORYLATION ; MECHANISMS
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
内容类型	期刊论文
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, Sch Med, Inst Immunol, Affiliated Hosp 2, Hangzhou, Zhejiang, Peoples R China 2.Zhejiang Univ, Sch Med, Dept Orthoped Surg, Affiliated Hosp 2, Hangzhou, Zhejiang, Peoples R China 3.Univ Chinese Acad Sci, Canc Hosp, Dept Med Oncol, Zhejiang Canc Hosp, Hangzhou, Peoples R China 4.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Hangzhou, Peoples R China 5.Shandong First Med Univ, Affiliated Hosp 1, Shandong Prov Key Lab Rheumat Dis & Translat Med, Jinan, Peoples R China 6.Shandong Prov Qianfoshan Hosp, Jinan, Peoples R China 7.Zhejiang Univ, Affiliated Hosp 2, Dept Radiat Oncol, Sch Med, Hangzhou, 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).