Endosomal TPC1-mediated Ca2+ nanodomains regulate transferrin receptor trafficking and iron homeostasis

• 成果类型: Article
• 署名作者: Burton, William J.; Lin, Alice; Morgan, Anthony J.; Davis, Lianne C.; Chen, Cheng-Chang; Galione, Antony
• 署名单位: University of Oxford; National Taiwan University; National Taiwan University; National Taiwan University Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2530835123
• 发表日期: 2026-07-21
• 页码: e2530835123
• 关键词: two-pore channel; calcium signaling; iron homeostasis; membrane trafficking; transferrin; 2-PORE CHANNELS; ion channels; calcium; NAADP; TPC1; activation; organelles; release; disease; voltage

摘要

Two-pore channel 1 (TPC1) is an endosomal Na+/Ca2+-selective channel implicated in membrane trafficking, endosome tubulation, and excitability, but how TPC1 regulates membrane trafficking is unknown. Using TPC1-null human cells, we demonstrate that TPC1 drives transferrin receptor (TfR) trafficking and recycling via Ca2+, and not Na+ fluxes or endosomal pH changes, since channel-targeted Ca2+-buffers inhibited trafficking, whereas a Na+-deficient Ca2+-permeable TPC1 mutant fully supported trafficking. TPC1 was unique since other Ca2+ sources did not support TfR trafficking. TPC1 activity depended on the lipid PI(3,5)P2, since trafficking was impaired by a lipid-insensitive TPC1 or inhibitors of lipid synthesis. Finally, a corollary of this reduced TfR trafficking is an iron-deficiency and storage phenotype in TPC1-deficient HeLa cells and mice. Our findings highlight endosomes as unique Ca2+ stores mobilized by a phosphoinositide-induced TPC1 channel that generates local Ca2+ nanodomains crucial for maintaining TfR trafficking and consequent iron homeostasis.