OSBP-Related Protein 5L Maintains Intracellular IP3/Ca2+ Signaling and Proliferation in T Cells by Facilitating PIP2 Hydrolysis

J Immunol. 2020 Mar 1;204(5):1134-1145. doi: 10.4049/jimmunol.1900671. Epub 2020 Jan 17.

Abstract

Phospholipase C (PLC) isoforms play central roles in signaling cascades by cleaving PIP2 into the second messengers IP3 and DAG. In this study, to our knowledge, we uncover that ORP5L interacts physically with PLCγ1 in T cells, extracts PIP2 from the plasma membrane via its ORD domain (OSBP-related domain), presents it to PLCγ1 (enabling IP3 generation), and eventually maintains intracellular Ca2+ homeostasis. Through this mechanism, ORP5L promotes T cell proliferation in a Ca2+-activated NFAT2-dependent manner. To our knowledge, our study uncovers a new key function of ORP5L as a critical cofactor for PLCγ1 catalysis and its crucial role in human T cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Signaling / immunology*
  • Cell Proliferation*
  • Female
  • Humans
  • Hydrolysis
  • Inositol 1,4,5-Trisphosphate / immunology*
  • Male
  • Phosphatidylinositol 4,5-Diphosphate / immunology*
  • Phospholipase C gamma / immunology
  • Receptors, Steroid / immunology*

Substances

  • Phosphatidylinositol 4,5-Diphosphate
  • Receptors, Steroid
  • oxysterol binding protein
  • Inositol 1,4,5-Trisphosphate
  • PLCG1 protein, human
  • Phospholipase C gamma