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

• 成果类型: Article
• 署名作者: Wang, Xiying; Geng, Ji; Rimal, Suman; Sui, Yuxiu; Pan, Jie; Qin, Zhenghong; Lu, Bingwei
• 署名单位: Nanjing Medical University; Stanford University; Soochow University - China; Soochow University - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12066
• DOI: 10.1073/pnas.2400531121
• 发表日期: 2024-09-24
• 关键词: cell-death; autophagy; ca2+; complex; mice; ap-1

摘要

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. Significance As a key target of the tumor suppressor p53, DRAM1 has been implicated in autophagy regulation. Whether DRAM1 performs cellular functions beyond autophagy remains elusive. Here, we show that DRAM1 is up-regulated in response to mitochondrial stress in models of neuromuscular diseases such as Parkinson's disease and amyotrophic lateral sclerosis (ALS). We show that excess DRAM1 disrupts ER structure, triggers ER stress, and induces ER-phagy. DRAM1 appears to interact with STIM1 to tether lysosomes and the ER and perturb STIM1 function in maintaining calcium homeostasis. Much of the detrimental effects of excess DRAM1 could be mitigated by the overexpression of STIM1. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response.