LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses

Ping Li, Meiqin Hu, Ce Wang, Xinghua Feng, Zhuang Zhuang Zhao, Ying Yang, Nirakar Sahoo, Mingxue Gu, Yexin Yang, Shiyu Xiao, Rajan Sah, Timothy L. Cover, Janet Chou, Raif Geha, Fernando Benavides, Richard I. Hume, Haoxing Xu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

LRRC8 family proteins on the plasma membrane play a critical role in cellular osmoregulation by forming volume-regulated anion channels (VRACs) necessary to prevent necrotic cell death. We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. LRRC8 proteins on lysosome membranes generate large lysosomal volume-regulated anion channel (Lyso-VRAC) currents in response to low cytoplasmic ionic strength conditions. When a double-leucine L706L707 motif at the C terminus of LRRC8A was mutated to alanines, normal plasma membrane VRAC currents were still observed, but Lyso-VRAC currents were absent. We used this targeting mutant, as well as pharmacological tools, to demonstrate that Lyso-VRAC currents are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis. Thus, Lyso-VRACs allow lysosomes of mammalian cells to act as the cell`s “bladder.” When Lyso-VRAC current was selectively eliminated, the extent of necrotic cell death to sustained stress was greatly increased, not only in response to hypoosmotic stress, but also to hypoxic and hypothermic stresses. Thus Lyso-VRACs play an essential role in enabling cells to mount successful homeostatic responses to multiple stressors.

Original languageEnglish
Pages (from-to)29155-29165
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Keywords

  • Lysosome | osmoregulation | chloride channel | vacuolation | exocytosis

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