Dataset Information

Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity

ABSTRACT: Chaperone-mediated autophagy (CMA), a selective autophagic process, plays a crucial role in maintaining intracellular quality and facilitating cellular responses to stress. While CMA has been implicated in finely regulating the stemness of normal stem cells, its significance in cancer stem cells (CSCs) remains largely undefined. In this study, we demonstrate that CMA is upregulated in patient-derived glioblastoma stem cells (GSCs), characterized by a notable increase in the levels of the CMA receptor, lysosome-associated membrane protein type 2A (LAMP2A). The enhanced stability of LAMP2A within GSC lysosomes is a result of MST4-mediated phosphorylation at residues T40, S97, and T136, which facilitates LAMP2A homotrimer formation and diminishes LAMP2A degradation by obstructing the interaction between LAMP2A and Cathepsin A. The contribution of CMA to the self-renewal and tumorigenic potential of GSCs is mediated by the upregulation of mTORC1 activity through the selective lysosomal degradation of its two negative modulators, TSC1 and TSC2. Furthermore, CMA is implicated in promoting resistance to immunotherapy in GBM by inhibiting the TET3-dependent enhancement of tumor cGAS and STING expression. Finally, the genetic or pharmacological inhibition of CMA exhibits a synergistic effect with immune checkpoint therapy in murine models of GBM. Our findings delineate an MST4-LAMP2A signaling pathway that modulates CMA activity and the malignancy of GSCs, with therapeutic targeting of this axis potentially overcoming immunotherapy resistance in GBM.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Epithelium

DISEASE(S): Brain Cancer

SUBMITTER: Yonghua Li

LAB HEAD: Tianzhi Huang

PROVIDER: PXD060464 | Pride | 2025-09-22

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	L2A-M4-new-Slot1-41-1-22325.d.zip	Other
	L2A-M4-old-Slot1-40-1-22323.d.zip	Other
	LAMP2A-interacting-proteins.xlsx	Xlsx
	checksum.txt	Txt

Items per page:

1 - 4 of 4

Similar Datasets

Project description:Background and aim: The molecular mechanisms underlying the progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) remain unclear; however, the role of autophagy in these mechanisms has attracted extensive attention. This study aimed to investigate the role of chaperone-mediated autophagy (CMA) in NAFL-to-NASH progression and elucidate the underlying mechanisms. Methods: Hepatic CMA activity was analyzed in patients with NASH and mouse models of NASH. LAMP2A was knocked down or overexpressed to assess the effects of hepatocyte-specific CMA on NAFL-to-NASH progression. Mice were fed a high-fat diet or a methionine–choline-deficient diet to induce NAFL or NASH. Palmitic acid was used to mimic lipotoxicity-induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via chromatin immunoprecipitation and dual-luciferase reporter assay. Results: Hepatic CMA activity was substantially low in patients and mice with NASH. Knockdown of LAMP2A resulted in hepatocyte-specific CMA deficiency, which promoted hepatic inflammation and fibrosis in mice with NASH. In addition, CMA deficiency exacerbated endoplasmic reticulum (ER) stress and hepatocyte damage in vivo and in vitro. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of HMGCR, a rate-limiting enzyme of cholesterol synthesis, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. Restoration of hepatocyte-specific CMA activity effectively ameliorated diet-induced NASH and ER stress in vivo and in vitro. FOXM1 negatively regulated the transcription of LAMP2A by directly binding to its promoter. Upregulation of FOXM1 impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious circle and promoting the development of NASH. Conclusions: This study highlights the role of the FOXM1/CMA/ER stress axis in NAFL-to-NASH progression and proposes novel therapeutic targets for NASH.

Dataset Information

Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets