The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes

Publication date: 27 June 2017
Source:Cell Reports, Volume 19, Issue 13
Author(s): Jian Wei, Ying-Yu Zhang, Jie Luo, Ju-Qiong Wang, Yu-Xia Zhou, Hong-Hua Miao, Xiong-Jie Shi, Yu-Xiu Qu, Jie Xu, Bo-Liang Li, Bao-Liang Song
Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown. Through amphotericin B-based selection, we isolated two cholesterol transport-defective cell lines. Subsequent whole-transcriptome-sequencing analysis revealed two cell lines bearing the same mutation in the vacuolar protein sorting 53 (Vps53) gene. Depletion of VPS53 or other subunits of the Golgi-associated retrograde protein (GARP) complex impaired NPC2 sorting to lysosomes and caused cholesterol accumulation. GARP deficiency blocked the retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR) to the trans-Golgi network. Further, Vps54 mutant mice displayed reduced cellular NPC2 protein levels and increased cholesterol accumulation, underscoring the physiological role of the GARP complex in cholesterol transport. We conclude that the GARP complex contributes to intracellular cholesterol transport by targeting NPC2 to lysosomes in a CI-MPR-dependent manner.

Graphical abstract

Teaser

Wei et al. find that the Golgi-associated retrograde protein (GARP) complex is involved in intracellular cholesterol transport. Inactivation of GARP impairs the retrieval of CI-MPR to the trans-Golgi network and decreases the transport of NPC2 to late endosomes/lysosomes, causing accumulation of cholesterol in cells.


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