LYVAC/PDZD8 is a lysosomal vacuolator

• 成果类型: Article
• 署名作者: Yang, Haoxiang; Xun, Jinrui; Li, Yajuan; Mondal, Awishi; Lv, Bo; Watkins, Simon C.; Shi, Lingyan; Tan, Jay Xiaojun
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of California System; University of California San Diego; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8656
• DOI: 10.1126/science.adz0972
• 发表日期: 2025-08-21
• 关键词: phosphatidylserine transport; membrane; proteins; vacuolization; localization; inhibitor; exchange; pi(4)p; driven; gui

摘要

Lysosomal vacuolation is commonly found in many pathophysiological conditions, but its molecular mechanisms and functions remain largely unknown. Here, we show that the endoplasmic reticulum (ER)-anchored lipid transfer protein PDZ domain-containing 8 (PDZD8), which we propose to be renamed as lysosomal vacuolator (LYVAC), is a general mediator of lysosomal vacuolation. Using human cell lines, we found that diverse lysosomal vacuolation inducers converged on lysosomal osmotic stress, triggering LYVAC recruitment through multivalent interactions. Stress-induced lysosomal lipid signaling contributed to both the recruitment and activation of LYVAC. By directly sensing lysosomal phosphatidylserine and cholesterol, the lipid transfer domain of LYVAC mediated directional ER-to-lysosome lipid movement, leading to osmotic membrane expansion of lysosomes. These findings uncover an essential mechanism for lysosomal vacuolation with broad implications in pathophysiology.