Genome-wide CRISPR screen reveals CLPTM1L as a lipid scramblase required for efficient glycosylphosphatidylinositol biosynthesis

Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2115083119. doi: 10.1073/pnas.2115083119.

Yicheng Wang ¹ ², Anant K Menon ³, Yuta Maki ⁴ ⁵, Yi-Shi Liu ⁶, Yugo Iwasaki ⁷, Morihisa Fujita ⁶, Paula A Guerrero ⁸ ⁹, Daniel Varó'n Silva ⁸ ⁹, Peter H Seeberger ⁸ ⁹, Yoshiko Murakami ¹, Taroh Kinoshita ¹ ² ¹⁰

Affiliations

1 Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan.
2 WPI Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan.
3 Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065.
4 Department of Chemistry, Graduate School of Science, Osaka University, 560-0043 Osaka, Japan.
5 Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, 560-0043 Osaka, Japan.
6 Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 214122 Wuxi, China.
7 Graduate School of Bioagricultural Science, Nagoya University, 464-8601 Aichi, Japan.
8 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
9 Department of Biochemistry and Chemistry, Freie Universität Berlin, 14195 Berlin, Germany.
10 Center for Infectious Disease Education and Research, Osaka University, 565-0871 Osaka, Japan.

PMID: 35344438 DOI: 10.1073/pnas.2115083119

Abstract

SignificanceScramblases translocate lipids across the lipid bilayer without consumption of ATP, thereby regulating lipid distributions in cellular membranes. Cytosol-to-lumen translocation across the endoplasmic reticulum (ER) membrane is a common process among lipid glycoconjugates involved in posttranslational protein modifications in eukaryotes. These translocations are thought to be mediated by specific ER-resident scramblases, but the identity of these proteins and the underlying molecular mechanisms have been elusive. Here, we show that CLPTM1L, an integral membrane protein with eight putative transmembrane domains, is the major lipid scramblase involved in efficient glycosylphosphatidylinositol biosynthesis in the ER membrane. Our results validate the long-standing hypothesis that lipid scramblases ensure the efficient translocations of lipid glycoconjugates across the ER membrane for protein glycosylation pathways.

Keywords

CLPTM1L; endoplasmic reticulum; glycobiology; glycosylphosphatidylinositol; scramblase.

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