The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
Xiying WangJi GengSuman RimalYuxiu SuiJie PanZhenghong QinBingwei LuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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.
Keyphrases
- endoplasmic reticulum
- oxidative stress
- protein kinase
- estrogen receptor
- signaling pathway
- cell death
- breast cancer cells
- dna damage
- endoplasmic reticulum stress
- induced apoptosis
- healthcare
- public health
- endothelial cells
- skeletal muscle
- intensive care unit
- cell cycle arrest
- binding protein
- small molecule
- bone marrow
- young adults
- diabetic rats
- long non coding rna
- poor prognosis
- amino acid
- protein protein
- extracorporeal membrane oxygenation
- heat stress
- risk assessment
- pi k akt