Cells adapt to extracellular acidic pH through TM9SF3-mediated PI(4,5)P2 flop

Keisuke Sako (), Yusuke V. Morimoto, Shin Morioka, Junya Hasegawa, Hiroyuki Nakajima, Moe Fukumoto, Yuya Nishida, Yasunori Shintani, Junko Sasaki, Takehiko Sasaki, Kazu Kikuchi and Naoki Mochizuki ()
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Keisuke Sako: National Cerebral and Cardiovascular Center Research Institute
Yusuke V. Morimoto: Kyushu Institute of Technology
Shin Morioka: Institute of Science Tokyo
Junya Hasegawa: Institute of Science Tokyo
Hiroyuki Nakajima: National Cerebral and Cardiovascular Center Research Institute
Moe Fukumoto: National Cerebral and Cardiovascular Center Research Institute
Yuya Nishida: National Cerebral and Cardiovascular Center Research Institute
Yasunori Shintani: National Cerebral and Cardiovascular Center Research Institute
Junko Sasaki: Institute of Science Tokyo
Takehiko Sasaki: Institute of Science Tokyo
Kazu Kikuchi: National Cerebral and Cardiovascular Center Research Institute
Naoki Mochizuki: National Cerebral and Cardiovascular Center Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The plasma membrane (PM), a physical barrier separating cells from their environment, responds to fluctuating extracellular environment through receptor-mediated signaling. While these pathways have been extensively studied, the role of PM lipids remains poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2), a multifunctional phospholipid, translocates from the inner to the outer leaflet of the PM in response to extracellular acidification. A genome-wide screening identifies Transmembrane 9 superfamily 3 (TM9SF3) as a critical regulator for PIP2 translocation. During zebrafish gastrulation, when intracellular pH increases and extracellular interstitial fluid pH decreases, mutant anterior axial mesoderm lacking Tm9sf3 exhibits disorganized collective cell migration due to impaired PIP2-dependent cytoskeletal organization. Our results demonstrate that TM9SF3 mediates the PIP2 translocation when cells encounter a low pH for adapting the cells to their environment. Given that “pH-dependent PIP2 translocation” is evolutionarily conserved, cells may broadly employ lipid topology as a strategy to respond to extracellular stimuli.

Date: 2025
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DOI: 10.1038/s41467-025-63524-w

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