2024/08/31 by Han Ben Niu, Masahiro Maruoka, Yuki Noguchi +2 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Alcoholism and Thiamine Deficiency #Endoplasmic Reticulum Stress and Disease #Erythrocyte Function and Pathophysiology
paper · pdf · doi:10.1038/s41467-024-51939-w
openalex publication_date 2024/08/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23
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. Phospholipid scrambling is used by cells to alter lipid asymmetry on the plasma membrane. Here, the authors performed CRISPR screenings to identify a heterodimer formed by Tmem63b and Slc19a2 that induces calcium-dependent phospholipid scrambling.