Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress

doi:10.1016/j.phymed.2023.154720

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	Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress
	Niu,Zhenpeng; Tang,Guihua; Wang,Xuenan; Yang,Xu; Zhao,Yueqin; Wang,Yinyuan; Liu,Qin; Zhang,Fan; Zhao,Yuhan; Ding,Xiao; Hao,Xiaojiang
	2023
发表期刊	PHYTOMEDICINE
ISSN	1618-095X
卷号	112 页码:154720
摘要	Background: Macroautophagy (henceforth autophagy) is the major form of autophagy, which delivers intracel-lular cargo to lysosomes for degradation. Considerable research has revealed that the impairment of lysosomal biogenesis and autophagic flux exacerbates the development of autophagy-related diseases. Therefore, reparative medicines restoring lysosomal biogenesis and autophagic flux in cells may have therapeutic potential against the increasing prevalence of these diseases. Purpose: The aim of the present study was thus to explore the effect of trigonochinene E (TE), an aromatic tet-ranorditerpene isolated from Trigonostemon flavidus, on lysosomal biogenesis and autophagy and to elucidate the potential underlying mechanism. Methods: Four human cell lines, HepG2, nucleus pulposus (NP), HeLa and HEK293 cells were applied in this study. The cytotoxicity of TE was evaluated by MTT assay. Lysosomal biogenesis and autophagic flux induced by 40 mu M TE were analyzed using gene transfer techniques, western blotting, real-time PCR and confocal micro-scopy. Immunofluorescence, immunoblotting and pharmacological inhibitors/activators were applied to deter-mine the changes in the protein expression levels in mTOR, PKC, PERK, and IRE1 alpha signaling pathways. Results: Our results showed that TE promotes lysosomal biogenesis and autophagic flux by activating the tran-scription factors of lysosomes, transcription factor EB (TFEB) and transcription factor E3 (TFE3). Mechanistically, TE induces TFEB and TFE3 nuclear translocation through an mTOR/PKC/ROS-independent and endoplasmic reticulum (ER) stress-mediated pathway. The PERK and IRE1 alpha branches of ER stress are crucial for TE-induced autophagy and lysosomal biogenesis. Whereas TE activated PERK, which mediated calcineurin dephosphoryla-tion of TFEB/TFE3, IRE1 alpha was activated and led to inactivation of STAT3, which further enhanced autophagy and lysosomal biogenesis. Functionally, knockdown of TFEB or TFE3 impairs TE-induced lysosomal biogenesis and autophagic flux. Furthermore, TE-induced autophagy protects NP cells from oxidative stress to ameliorate intervertebral disc degeneration (IVDD). Conclusions: Here, our study showed that TE can induce TFEB/TFE3-dependent lysosomal biogenesis and auto-phagy via the PERK-calcineurin axis and IRE1 alpha-STAT3 axis. Unlike other agents regulating lysosomal biogenesis and autophagy, TE showed limited cytotoxicity, thereby providing a new direction for therapeutic opportunities to use TE to treat diseases with impaired autophagy-lysosomal pathways, including IVDD.
关键词	Lysosomal biogenesis Autophagy TFEB TFE3 ER stress IVDD STAT3 TFE3
学科领域	Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
DOI	10.1016/j.phymed.2023.154720
收录类别	SCI
WOS记录号	WOS:000949810100001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75399
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Niu,Zhenpeng,Tang,Guihua,Wang,Xuenan,et al. Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress[J]. PHYTOMEDICINE,2023,112:154720.
APA	Niu,Zhenpeng.,Tang,Guihua.,Wang,Xuenan.,Yang,Xu.,Zhao,Yueqin.,...&Hao,Xiaojiang.(2023).Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress.PHYTOMEDICINE,112,154720.
MLA	Niu,Zhenpeng,et al."Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress".PHYTOMEDICINE 112(2023):154720.

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