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

Hu, Ao, Zhao, Xue-Tong, Tu, Heng, Xiao, Ting, Fu, Ting, Wang, Yan, Liu, Yong, Shi, Xiong-Jie, Luo, Jie, Song, Bao-Liang·2018·Journal of Lipid Research
DOI 10.1194/jlr.m082149
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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)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 α (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 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)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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Research works printed but not linked: 28

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Metadata

Authors
Hu, A., Zhao, X.-T., Tu, H., Xiao, T., Fu, T., Wang, Y., Liu, Y., Shi, X.-J., Luo, J., & Song, B.-L.
ORCID
Luo, Jie
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2018-03
Volume
59
Issue
3
Pages
507-514
ISSN
0022-2275
DOI
10.1194/jlr.m082149
Cited by
81
References
0
Language
en
Licence
Funders
  • Ministry of Science and Technology of China (2016YFA0500100)
  • National Natural Science Foundation of China (91754102, 31771568, 31600651, 31690102, 31701030)
  • China Postdoctoral Science Foundation (2017M622508)
  • Ministry of Education of China (B16036)
  • Natural Science Foundation of Hubei Province (2016CFA012)

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