The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.

Autor:	Wang X; Department of Psychiatry, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing 210029, China., Geng J; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305., Rimal S; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305., Sui Y; Department of Psychiatry, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing 210029, China., Pan J; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305., Qin Z; Institute of Health Technology, Global Institute of Software Technology, Suzhou 215163, China.; Department of Pharmacology and Laboratory of Aging and Nervous Diseases, School of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Lu B; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Sep 24; Vol. 121 (39), pp. e2400531121. Date of Electronic Publication: 2024 Sep 18.
DOI:	10.1073/pnas.2400531121
Abstrakt:	It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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