Phospholipid scrambling induced by an ion channel/metabolite transporter complex

Han Niu, Masahiro Maruoka, Yuki Noguchi, Hidetaka Kosako and Jun Suzuki ()
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Han Niu: Yoshida-Honmachi
Masahiro Maruoka: Yoshida-Honmachi
Yuki Noguchi: Yoshida-Honmachi
Hidetaka Kosako: Tokushima University
Jun Suzuki: Yoshida-Honmachi

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Cells establish the asymmetrical distribution of phospholipids and alter their distribution by phospholipid scrambling (PLS) to adapt to environmental changes. Here, we demonstrate that a protein complex, consisting of the ion channel Tmem63b and the thiamine transporter Slc19a2, induces PLS upon calcium (Ca2+) stimulation. Through revival screening using a CRISPR sgRNA library on high PLS cells, we identify Tmem63b as a PLS-inducing factor. Ca2+ stimulation-mediated PLS is suppressed by deletion of Tmem63b, while human disease-related Tmem63b mutants induce constitutive PLS. To search for a molecular link between Ca2+ stimulation and PLS, we perform revival screening on Tmem63b-overexpressing cells, and identify Slc19a2 and the Ca2+-activated K+ channel Kcnn4 as PLS-regulating factors. Deletion of either of these genes decreases PLS activity. Biochemical screening indicates that Tmem63b and Slc19a2 form a heterodimer. These results demonstrate that a Tmem63b/Slc19a2 heterodimer induces PLS upon Ca2+ stimulation, along with Kcnn4 activation.

Date: 2024
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DOI: 10.1038/s41467-024-51939-w

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