PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis.

Abstract:

:The transport of LDL-derived cholesterol from lysosomes to peroxisomes is facilitated by membrane contacts formed between the lysosomal protein synaptotagmin VII and the peroxisomal lipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P2]. Here, we used RNA interference to search for regulators of PI(4,5)P2 and to study the effects of altered PI(4,5)P2 homeostasis on cholesterol transport. We found that knockdown of phosphatidylinositol 5-phosphate 4-kinase type-2 α (PIP4K2A) reduced peroxisomal PI(4,5)P2 levels, decreased lysosome-peroxisome membrane contacts, and increased accumulation of lysosomal cholesterol in human SV-589 fibroblasts. Forced expression of peroxisome-localized, kinase-active PIP4K2A in the knockdown cells reduced cholesterol accumulation, and in vitro addition of recombinant PIP4K2A restored membrane contacts. These results suggest that PIP4K2A plays a critical role in intracellular cholesterol transport by upregulating PI(4,5)P2 levels in the peroxisomal membrane. Further research into PIP4K2A activity may inform future therapeutic interventions for managing lysosomal storage disorders.

journal_name

J Lipid Res

authors

Hu A,Zhao XT,Tu H,Xiao T,Fu T,Wang Y,Liu Y,Shi XJ,Luo J,Song BL

doi

10.1194/jlr.M082149

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

507-514

issue

3

eissn

0022-2275

issn

1539-7262

pii

jlr.M082149

journal_volume

59

pub_type

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