Abstract
Cholesterol, which is endocytosed to the late endosome (LE)/lysosome, is delivered to other organelles through vesicular and nonvesicular transport mechanisms. In this study, we discuss a novel mechanism of cholesterol transport from recycling endosomes (REs) to the trans-Golgi network (TGN) through RELCH/KIAA1468, which is newly identified in this study as a Rab11-GTP- and OSBP-binding protein. After treating cells with 25-hydroxycholesterol to induce OSBP relocation from the cytoplasm to the TGN, REs accumulated around the TGN area, but this accumulation was diminished in RELCH- or OSBP-depleted cells. Cholesterol content in the TGN was decreased in Rab11-, RELCH-, and OSBP-depleted cells and increased in the LE/lysosome. According to in vitro reconstitution experiments, RELCH tethers Rab11-bound RE-like and OSBP-bound TGN-like liposomes and promotes OSBP-dependent cholesterol transfer from RE-like to TGN-like liposomes. These data suggest that RELCH promotes nonvesicular cholesterol transport from REs to the TGN through membrane tethering.
Highlights
Most mammalian cells acquire cholesterol through the endocytosis of plasma lipoproteins such as low-density lipoprotein (LDL)
We observed that RELCH colocalized with Rab11- and transferrin receptor (TfnR)-positive recycling endosomes (REs) but not with the early/sorting endosomal protein EEA1, the trans-Golgi network (TGN) protein p230, or the late endosome (LE)/lysosome proteins cationdependent mannose-6-phosphate receptor (CD-MPR) and Lamp2
We identified that RELCH is a Rab11-GTP binding protein and revealed the interaction between RELCH and oxysterol-binding protein (OSBP)
Summary
Most mammalian cells acquire cholesterol through the endocytosis of plasma lipoproteins such as low-density lipoprotein (LDL). Accumulating evidence suggests that intracellular cholesterol transport is mediated by the following two mechanisms: vesicular and nonvesicular transport. SNARE proteins, which mediate vesicle/membrane fusion, are involved in cholesterol delivery from the endosome to the trans-Golgi network (TGN; Urano et al, 2008). Oxysterol binding protein–related proteins (ORPs) are potential key regulators. The oxysterol-binding protein (OSBP)-related ligand binding domain (ORP-related domain [ORD]) of ORPs binds lipids such as oxysterol, ergosterol, cholesterol, phosphatidylinositol (PI), and phosphatidylserine (PS; Im et al, 2005; Maeda et al, 2013; Mesmin et al, 2013; Liu and Ridgway, 2014), suggesting that ORPs function as lipid sensors or lipid transfer proteins at MCSs. OSBP, which is a TGN-localized protein, is among the best characterized ORPs. OSBP transfers cholesterol from the ER to the TGN through the countertransfer of PI 4-phosphate (PI4P) at ER–Golgi MCSs (Mesmin et al, 2013)
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