Details

Autor(en) / Beteiligte

• Wei, Jian
• Zhang, Ying-Yu
• Luo, Jie
• Wang, Ju-Qiong
• Zhou, Yu-Xia
• Miao, Hong-Hua
• Shi, Xiong-Jie
• Qu, Yu-Xiu
• Xu, Jie
• Li, Bo-Liang
• Song, Bao-Liang

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2017-06, Vol.19 (13), p.2823-2835

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Cholesterol transport-defective cells harbor a mutation in VPS53•VPS53 and other GARP complex subunits are required for targeting NPC2 to lysosomes•The GARP complex directs NPC2 sorting by modulation of CI-MPR retrieval to the Golgi•Cholesterol homeostasis is disrupted in GARP-deficient wobbler mice 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.