2. Academic Validation
  3. Zinc transport via ZNT5-6 and ZNT7 is critical for cell surface glycosylphosphatidylinositol-anchored protein expression

Zinc transport via ZNT5-6 and ZNT7 is critical for cell surface glycosylphosphatidylinositol-anchored protein expression

  • J Biol Chem. 2022 Jun;298(6):102011. doi: 10.1016/j.jbc.2022.102011.
Takumi Wagatsuma 1,  Keiko Shimotsuma 1,  Akiko Sogo 2,  Risa Sato 3,  Naoya Kubo 1,  Sachiko Ueda 1,  Yasuo Uchida 3,  Masato Kinoshita 2,  Taiho Kambe 4
Affiliations

Affiliations

  • 1 Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
  • 2 Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
  • 3 Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 4 Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan. Electronic address: [email protected].
PMID: 35525268 DOI: 10.1016/j.jbc.2022.102011
Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins play crucial roles in various Enzyme activities, cell signaling and adhesion, and immune responses. While the molecular mechanism underlying GPI-anchored protein biosynthesis has been well studied, the role of zinc transport in this process has not yet been elucidated. Zn transporter (ZNT) proteins mobilize cytosolic zinc to the extracellular space and to intracellular compartments. Here, we report that the early secretory pathway ZNTs (ZNT5-ZNT6 heterodimers [ZNT5-6] and ZNT7-ZNT7 homodimers [ZNT7]), which supply zinc to the lumen of the early secretory pathway compartments are essential for GPI-anchored protein expression on the cell surface. We show, using overexpression and gene disruption/re-expression strategies in cultured human cells, that loss of ZNT5-6 and ZNT7 zinc transport functions results in significant reduction in GPI-anchored protein levels similar to that in mutant cells lacking phosphatidylinositol glycan anchor biosynthesis (PIG) genes. Furthermore, medaka fish with disrupted Znt5 and Znt7 genes show touch-insensitive phenotypes similar to zebrafish Pig mutants. These findings provide a previously unappreciated insight into the regulation of GPI-anchored protein expression and protein quality control in the early secretory pathway.

Keywords

ER quality control; ZNT; cell surface; early secretory pathway; ectoenzyme; glycosylphosphatidylinositol (GPI anchor); phosphatidylinositol glycan anchor biosynthesis (PIG); transporter; zinc.

Figures