Transport through recycling endosomes requires EHD1 recruitment by a phosphatidylserine translocase

Shoken Lee, Yasunori Uchida, Jiao Wang, Tatsuyuki Matsudaira, Takatoshi Nakagawa, Takuma Kishimoto, Kojiro Mukai, Takehiko Inaba, Toshihide Kobayashi, Robert S. Molday, Tomohiko Taguchi, Hiroyuki Arai

研究成果: Article査読

67 被引用数 (Scopus)

抄録

P4-ATPases translocate aminophospholipids, such as phosphatidylserine (PS), to the cytosolic leaflet of membranes. PS is highly enriched in recycling endosomes (REs) and is essential for endosomal membrane traffic. Here, we show that PS flipping by an RE-localized P4-ATPase is required for the recruitment of the membrane fission protein EHD1. Depletion of ATP8A1 impaired the asymmetric transbilayer distribution of PS in REs, dissociated EHD1 from REs, and generated aberrant endosomal tubules that appear resistant to fission. EHD1 did not show membrane localization in cells defective in PS synthesis. ATP8A2, a tissue-specific ATP8A1 paralogue, is associated with a neurodegenerative disease (CAMRQ). ATP8A2, but not the disease-causative ATP8A2 mutant, rescued the endosomal defects in ATP8A1-depleted cells. Primary neurons from Atp8a2-/- mice showed a reduced level of transferrin receptors at the cell surface compared to Atp8a2+/+ mice. These findings demonstrate the role of P4-ATPase in membrane fission and give insight into the molecular basis of CAMRQ. Synopsis The aminophospholipid translocase ATP8A1 enriches phosphatidylserine at the cytosolic leaflet of recycling endosomes, recruiting fission protein EHD1. Phosphatidylserine translocation is required for cargo sorting and membrane fission, a process perturbed in CAMRQ disease-associated ATP8A2 mutant cells. P4-ATPase ATP8A1 flips phosphatidylserine (PS) to the cytosolic leaflet of recycling endosomes (REs). PS recruits membrane fission protein EHD1 to REs. The ATP8A1/PS/EHD1 axis regulates membrane traffic from REs. Membrane traffic defects at REs may underlie a neurodegenerative disease associated with ATP8A2 mutations. The aminophospholipid translocase ATP8A1 enriches phosphatidylserine at the cytosolic leaflet of recycling endosomes, recruiting fission protein EHD1. Phosphatidylserine translocation is required for cargo sorting and membrane fission, a process perturbed in CAMRQ disease-associated ATP8A2 mutant cells.

本文言語English
ページ(範囲)669-688
ページ数20
ジャーナルEMBO Journal
34
5
DOI
出版ステータスPublished - 2015 3 4
外部発表はい

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

フィンガープリント 「Transport through recycling endosomes requires EHD1 recruitment by a phosphatidylserine translocase」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル