Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy-lysosome path
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Chinese Medicine Open Access
REVIEW
Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy‑lysosome pathway Jie Xu, Xiao‑Qi Zhang* and Zaijun Zhang*
Abstract Autophagy is a highly conserved degradation process for long-lived intracellular proteins and organelles mediated by lysosomes. Deficits in the autophagy-lysosome pathway (ALP) have been linked to a variety of human diseases, including neurodegenerative diseases, lysosomal storage disorders, and cancers. Transcription factor EB (TFEB) has been identified as a major regulator of autophagy and lysosomal biogenesis. Increasing evidence has demonstrated that TFEB activation can promote the clearance of toxic protein aggregates and regulate cellular metabolism. Tradi‑ tional Chinese medicine (TCM)-derived natural products as important sources for drug discovery have been widely used for the treatment of various diseases associated with ALP dysfunction. Herein, we review (1) the regulation of TFEB and ALP; (2) TFEB and ALP dysregulation in human diseases; (3) TFEB activators from natural products and their potential uses. Keywords: TFEB, Autophagy, Autophagy-lysosome pathway, Natural products, TFEB agonists Background There are two major protein degradation pathways in eukaryotic cells. The ubiquitin-proteasome system (UPS) is responsible for degrading short-lived soluble proteins, while the autophagy-lysosome pathway (ALP) is mainly responsible for regulating and recycling long-lived insoluble proteins and organelles. Autophagy is a lysosomemediated bulk degradation process that occurs in all eukaryotic cells from yeasts to mammals [1]. Three main types of autophagy are currently recognized: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Although the mechanisms of the three subtypes are different, they have similar stimuli, such
*Correspondence: [email protected]; [email protected] Guangdong Provincial Engineering Research Center for Modernization of TCM, Institute of New Drug Research, Guangdong Provincial Key Laboratory of Pharmacodynamic, Constituents of TCM and New Drug Research, College of Pharmacy, Jinan University, 510632 Guangzhou, People’s Republic of China
as environmental stress, nutrient starvation, oxidative stress, and infection [2]. In general, autophagy is divided into different stages, including initiation, elongation and maturation. Autophagy is initiated by the formation of a doublemembrane structure called a phagophore. In the initiation of autophagy, there are two important autophagy initiation complexes. One is the UN51-like Ser/Thr kinases complex (ULK) [3]. Another essential autophagy complex for autophagosome formation is the class III phosphatidylinositol 3-kinase (PI3K) complex that is also called the beclin 1 complex [4, 5]. Then, two ubiquitin-like conjugation systems called the ATG12-ATG5-ATG16 complex and LC3/Atg8 are involved in the elongation of autophagy. The doublemembrane phagophore elongates to engulf various intracellular cargos, including t
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