Ca2+- sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress

• 成果类型: Article
• 署名作者: Chen, Wei; Motsinger, Madeline M.; Li, Jiaqian; Bohannon, Kevin P.; Ab, Phyllis I. Hanson
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15382
• DOI: 10.1073/pnas.2318412121
• 发表日期: 2024-05-28
• 关键词: leucine methyl-ester; dipeptidyl peptidase-i; protein alg-2; cytotoxic lymphocytes; structural basis; vipp1; alix; maintenance; mechanism; sites

摘要

Lysosomes are central players in cellular catabolism, signaling, and metabolic lation. Cellular and environmental stresses that damage lysosomal membranes compromise their function and release toxic content into the cytoplasm. Here, examine how cells respond to osmotic stress within lysosomes. Using sensitive assays of lysosomal leakage and rupture, we examine acute effects of the osmotic disruptant glycyl - L - phenylalanine 2 - naphthylamide (GPN). Our findings reveal that low concentrations of GPN rupture a small fraction of lysosomes, but surprisingly trigger release from nearly all. Chelating cytoplasmic Ca 2+ makes lysosomes more sensitive GPN - induced rupture, suggesting a role for Ca 2+ in lysosomal membrane resilience. GPN - elicited Ca 2+ release causes the Ca 2+ - sensor Apoptosis Linked Gene - 2 (ALG along with Endosomal Sorting Complex Required for Transport (ESCRT) proteins interacts with, to redistribute onto lysosomes. Functionally, ALG - 2, but not its ESCRT binding - disabled Delta GF 122 splice variant, increases lysosomal resilience to osmotic stress. Importantly, elevating juxta - lysosomal Ca 2+ without membrane damage by activating TRPML1 also recruits ALG - 2 and ESCRTs, protecting lysosomes from subsequent osmotic rupture. These findings reveal that Ca 2+ , through ALG - 2, helps bring ESCRTs to lysosomes to enhance their resilience and maintain organelle integrity in the of osmotic stress.