Journal
JOURNAL OF LIPID RESEARCH
Volume 59, Issue 3, Pages 507-514Publisher
ELSEVIER
DOI: 10.1194/jlr.M082149
Keywords
ATP binding cassette transporter D1; lysosomes; lysosome-peroxisome membrane contact; Syt7; synaptotagmin
Categories
Funding
- Ministry of Science and Technology of China [2016YFA0500100]
- National Natural Science Foundation of China [91754102, 31771568, 31600651, 31690102, 31701030]
- China Postdoctoral Science Foundation [2017M622508]
- 111 Project of the Ministry of Education of China [B16036]
- Natural Science Foundation of Hubei Province [2016CFA012, 2017CFB617]
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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)P-2]. Here, we used RNA interference to search for regulators of PI(4,5)P-2 and to study the effects of altered PI(4,5)P-2 homeostasis on cholesterol transport. We found that knockdown of phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A) reduced peroxisomal PI(4,5)P-2 levels, decreased lysosome-peroxisome membrane contacts, and increased accumulation of lysosomal cholesterol in human SV-589 fibroblasts. Forced expression of peroxisomelocalized, 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)P-2 levels in the peroxisomal membrane. Further research into PIP4K2A activity may inform future therapeutic interventions for managing lysosomal storage disorders.
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