Department of Psychiatry, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2400531121. doi: 10.1073/pnas.2400531121. Epub 2024 Sep 18.
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.
已证实，DNA 损伤调控自噬调节剂 1（DRAM1）是一种溶酶体蛋白和 p53 的靶标，参与自噬。DRAM1 除了自噬之外的细胞功能仍然难以捉摸。在这里，我们显示了 p53 依赖性上调在线粒体损伤诱导的帕金森病（PD）模型中的 DRAM1，并通过 DRAM1 加重疾病表型。我们发现 DRAM1 的溶酶体位置依赖于其完整的结构，包括面向细胞质的 C 末端结构域。过量的 DRAM1 会破坏内质网（ER）结构，引发 ER 应激，并诱导保护性 ER 自噬。在机制上，DRAM1 与基质相互作用分子 1（STIM1）相互作用，将溶酶体固定到 ER 上，并破坏 STIM1 维持细胞内钙稳态的功能。STIM1 过表达通过恢复钙稳态、内质网应激反应、ER 自噬和 AMP 激活的蛋白激酶（AMPK）-Unc-51 样自噬激活激酶 1（ULK1）信号来促进细胞健康，在细胞中过量表达 DRAM1。因此，通过促进溶酶体和 ER 之间的细胞器接触，DRAM1 调节 ER 结构和功能以及应激下的细胞存活。我们的结果表明，作为一种溶酶体蛋白，DRAM1 在细胞内稳态和应激反应中发挥多种作用。这些发现可能对我们理解 p53/DRAM1 轴在从癌症到神经退行性疾病等人类疾病中的作用具有重要意义。
