bims-lycede 2024-09-22 papers

Issue of 2024‒09‒22
two papers selected by
Sofía Peralta, Universidad Nacional de Cuyo

EMBO J. 2024 Sep 16.

Non-autophagic Golgi-LC3 lipidation facilitates TFE3 stress response against Golgi dysfunction.

Jaemin Kang, Cathena Meiling Li, Namhoon Kim, Jongyeon Baek, Yong-Keun Jung.

Lipidated ATG8/LC3 proteins are recruited to single membrane compartments as well as autophagosomes, supporting their functions. Although recent studies have shown that Golgi-LC3 lipidation follows Golgi damage, its molecular mechanism and function under Golgi stress remain unknown. Here, by combining DLK1 overexpression as a new strategy for induction of Golgi-specific LC3 lipidation, and the application of Golgi-damaging reagents, we unravel the mechanism and role of Golgi-LC3 lipidation. Upon DLK1 overexpression, LC3 is lipidated on the Golgi apparatus in an ATG12-ATG5-ATG16L1 complex-dependent manner; a post-Golgi trafficking blockade is the primary cause of this lipidation. During Golgi stress, ATG16L1 is recruited through its interaction with V-ATPase for Golgi-LC3 lipidation. After post-Golgi trafficking inhibition, TFE3, a key regulator of the Golgi stress response, is translocated to the nucleus. Defects in LC3 lipidation disrupt this translocation, leading to an attenuation of the Golgi stress response. Together, our results reveal the mechanism and unexplored function of Golgi-LC3 lipidation in the Golgi stress response.

Keywords: CASM; Golgi Apparatus; Golgi Stress Response; Post-Golgi Trafficking; V-ATPase

DOI: https://doi.org/10.1038/s44318-024-00233-y

Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2400531121

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

Xiying Wang, Ji Geng, Suman Rimal, Yuxiu Sui, Jie Pan, Zhenghong Qin, Bingwei Lu.

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.

Keywords: DRAM1; ER; ER-phagy; calcium homeostasis; lysosome

DOI: https://doi.org/10.1073/pnas.2400531121