Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase

Mol Biol Cell. 2012 Apr;23(8):1533-45. doi: 10.1091/mbc.E11-06-0553. Epub 2012 Feb 15.


Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct phosphatidylinositol 4-kinases (PI4Ks) play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi caused accumulation of LIMP-2 in this compartment, and PI4KIIIβ was found to be responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIα blocked trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIα depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIβ inhibitors. These studies identified PI4KIIIβ and PI4KIIα as important regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid homeostasis by phosphoinositides.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / genetics
  • 1-Phosphatidylinositol 4-Kinase / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Endosomes / metabolism
  • Gaucher Disease / enzymology
  • Gaucher Disease / metabolism
  • Glucosylceramidase / metabolism*
  • Golgi Apparatus / enzymology
  • Golgi Apparatus / metabolism
  • HEK293 Cells
  • Humans
  • Lysosomal-Associated Membrane Protein 2 / metabolism*
  • Lysosomes / metabolism*
  • Minor Histocompatibility Antigens
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Transport
  • RNA Interference
  • RNA, Small Interfering


  • Lysosomal-Associated Membrane Protein 2
  • Minor Histocompatibility Antigens
  • RNA, Small Interfering
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-Phosphatidylinositol 4-Kinase
  • phosphatidylinositol phosphate 4-kinase
  • Glucosylceramidase