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

Xiying Wang1, Ji Geng2, Suman Rimal2

  • 1Department of Psychiatry, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing 210029, China.

Proceedings of the National Academy of Sciences of the United States of America
|September 18, 2024
PubMed

Insights

DNA Damage Regulated Autophagy Modulator 1 (DRAM1) protein, a p53 target, disrupts cellular homeostasis and worsens Parkinson's disease models by affecting ER-lysosome interactions. Restoring calcium balance counteracts these harmful effects.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Molecular Biology

Background:

  • DNA Damage Regulated Autophagy Modulator 1 (DRAM1) is a p53 target involved in autophagy.
  • The broader cellular functions of DRAM1 are not fully understood.
  • Parkinson's disease (PD) involves mitochondrial dysfunction and cellular stress.

Purpose of the Study:

  • Investigate DRAM1's role beyond autophagy, particularly in Parkinson's disease.
  • Elucidate the mechanism by which DRAM1 affects cellular homeostasis and stress responses.
  • Explore the therapeutic potential of modulating DRAM1 activity.

Main Methods:

  • Utilized Parkinson's disease models with induced mitochondrial damage.
  • Examined DRAM1 expression and localization in response to cellular stress.
  • Investigated DRAM1's interaction with endoplasmic reticulum (ER) and lysosomes.
  • Assessed the impact of DRAM1 on ER structure, ER stress, and ER-phagy.
  • Analyzed the role of stromal interacting molecule 1 (STIM1) in DRAM1-mediated effects.

Main Results:

  • DRAM1 is upregulated in p53-dependent manner in PD models, exacerbating disease phenotypes.
  • Excess DRAM1 disrupts ER structure, induces ER stress, and promotes ER-phagy.
  • DRAM1 interacts with STIM1, tethering lysosomes to the ER and impairing calcium homeostasis.
  • STIM1 overexpression rescues cellular health by restoring calcium balance and ER stress response.

Conclusions:

  • DRAM1 plays a significant role in cellular homeostasis and stress response beyond autophagy.
  • DRAM1's interaction with STIM1 modulates ER-lysosome contact, impacting ER function and cell survival.
  • The p53/DRAM1 axis is implicated in neurodegenerative diseases, offering potential therapeutic targets.
Keywords:
DRAM1ERER-phagycalcium homeostasislysosome

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