Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation

doi:10.1016/j.phrs.2021.105679

	Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation
	Bao, Weilian 1,3; Liu, Xiaohong 2; You, Yan 1,3,4; Hou, Hui 2; Wang, Xu 1,3; Zhang, Sulin 2; Li, Haidong 1,3; Feng, Guize 1,3; Cao, Xinyu 1,3; Jiang, Hualiang 2
刊名	PHARMACOLOGICAL RESEARCH
	2021-07-01
卷号	169 页码:11
关键词	SNX10 IBD Macrophage PIKfyve TBK1 PPI inhibitor
ISSN号	1043-6618
DOI	10.1016/j.phrs.2021.105679
通讯作者	Jiang, Hualiang(hljiang@simm.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn) ; Shen, Xiaoyan(shxiaoy@fudan.edu.cn)
英文摘要	Sorting nexin 10 (SNX10) has been reported as a critical regulator in macrophage function, and germline SNX10 knockout effectively alleviated mouse colitis. Here, we investigated the precise role of SNX10 in inflammatory responses in macrophages in mouse colitis, and explored the druggability of SNX10 as a therapeutic target for inflammatory bowel disease (IBD). Our results revealed that myeloid-specific SNX10 deletion alleviated inflammation and pathological damage induced by dextran sulfate sodium (DSS). In vitro experiments showed that SNX10 deletion contributed to inflammation elimination by inhibiting PlKfyve-mediated TANK-binding kinase 1 (TBK1)/c-Rel signaling activation. Further study provided rational mechanism that SNX10 was required for the recruitment of PIKfyve to the TRIF-positive endosomes, through which PIKfyve activated TBK1/c-Rel for LPS-induced inflammation response. Based on the structure of SNX10, we discovered a new small-molecule inhibitor DC-5X029, which targeted SNX10 to block the SNX10-PIKfyve interaction, thereby decreased the TBK1/c-Rel signaling activation. Additionally, therapeutic efficiency of DC-5X029 was evaluated in both DSS-induced and IL10-deficient mouse colitis models. Our data demonstrate a new mechanism by which SNX10-PIKfyve interaction regulates LPS-induced inflammation response in macrophages via the TBK1/c-Rel signaling pathway. In vivo and in vitro pharmacological studies of SNX10 protein-protein interaction (PPI) inhibitor DC-5X029 demonstrate the feasibility of targeting SNX10 in IBD treatment.
资助项目	National Natural Science Foundation of China[81773744] ; National Natural Science Foundation of China[81973523] ; National Natural Science Foundation of China[81573441] ; National Natural Science Foundation of China[81371923] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020368] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1903KF-05] ; Fudan-SIMM Joint Research Fund[FU-SIMM20183002]
WOS关键词	C-REL ; ULCERATIVE-COLITIS ; KINASE ; PHOSPHORYLATION ; INDUCTION ; BACTERIA ; APILIMOD
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS记录号	WOS:000663005100056
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296881]
专题	中国科学院上海药物研究所
通讯作者	Jiang, Hualiang; Zheng, Mingyue; Shen, Xiaoyan
作者单位	1.Fudan Univ, Sch Pharm, Dept Pharmacol, Minist Educ, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 3.Fudan Univ, Sch Pharm, Key Lab Smart Drug Delivery, Minist Educ, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 4.Natl Inst Allergy & Infect, NIH, Rockville, MD USA
推荐引用方式 GB/T 7714	Bao, Weilian,Liu, Xiaohong,You, Yan,et al. Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation[J]. PHARMACOLOGICAL RESEARCH,2021,169:11.
APA	Bao, Weilian.,Liu, Xiaohong.,You, Yan.,Hou, Hui.,Wang, Xu.,...&Shen, Xiaoyan.(2021).Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation.PHARMACOLOGICAL RESEARCH,169,11.
MLA	Bao, Weilian,et al."Targeting sorting nexin 10 improves mouse colitis via inhibiting PIKfyve-mediated TBK1/c-Rel signaling activation".PHARMACOLOGICAL RESEARCH 169(2021):11.