Oxysterol-binding protein–related protein 5 (ORP5) promotes cell proliferation by activation of mTORC1 signaling

Abstract

Oxysterol-binding protein (OSBP) and OSBPrelated proteins (ORPs) constitute a large family of proteins that mainly function in lipid transport and sensing. ORP5 is an endoplasmic reticulum (ER)-anchored protein implicated in lipid transfer at the contact sites between the ER and other membranes. Recent studies indicate that ORP5 is also involved in cancer cell invasion and tumor progression. However, the molecular mechanism underlying ORP5's involvement in cancer is unclear. Here, we report that ORP5 promotes cell proliferation and motility of HeLa cells, an effect that depends on its functional OSBP-related domain (ORD). We also found that ORP5 depletion or substitutions of key residues located within ORP5-ORD and responsible for interactions with lipids interfered with cell proliferation, migration and invasion. ORP5 interacted with the protein mechanistic target of rapamycin (mTOR), and this interaction also required ORP5-ORD. Of note, whereas ORP5 overexpression induced mTOR complex 1 (mTORC1) activity, ORP5 down-regulation had the opposite effect. Finally, ORP5-depleted cells exhibited impaired mTOR localization to lysosomes, which may have accounted for the blunted mTORC1 activation. Together, our results suggest that ORP5 expression is positively correlated with mTORC1 signaling and that ORP5 stimulates cell proliferation, at least in part, by activating mTORC1.

Orp5/8 and Mib/Micos Link Er-Mitochondria and Intramitochondrial Contacts for Non-Vesicular Transport of Phosphatidylserine

“…Accumulation of mitochondrial Ca 2+ has been shown to be involved in both 510 apoptotic cell death and senescence (permanent cell proliferation arrest) (Wiel,511 Lallet-Daher et al, 2014). Interestingly, it also has been shown that ORP5 expression 512 promotes cell proliferation (Du, Zadoorian et al, 2018). As our data show a new role 513 of ORP5 in regulating Ca 2+ import to mitochondria at ER-mitochondria contact sites 514 ( Fig.…”

ORP5 localizes to ER–lipid droplet contacts and regulates the level of PI(4)P on lipid droplets

“…5, I-K). In contrast, ORP5 mutants deficient for PS (L389D) transport or PI(4)P/PI(4,5)P 2 binding (H478A/H479A; Chung et al, 2015;de Saint-Jean et al, 2011;Du et al, 2018;Galmes et al, 2016;Ghai et al, 2017;Maeda et al, 2013;Sohn et al, 2018) failed to reduce the size of LDs in ORP5 KO cells (Fig. 5, L and M), although L389D mutant seemed to have reduced the sizes of the LD population with a diameter >2 µm ( Fig.…”

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

“…Mechanistically, ORP5 was found to interact with NPC1 on late endosomes/lysosomes and transfer cholesterol to the ER and diminished ORP5 expression resulted in the accumulation of cholesterol in these late endocytic organelles (15). It was subsequently discovered that the ORP5 ORD is also able to interact with mammalian target of rapamycin (mTOR) on late endosomes/lysosomes, suggesting that ORP5 and cholesterol may play a role in nutrient sensing at the ER-late endosomal/lysosomal MCS (87). Together, ORP5 appears to function at several MCS and possess an array of lipid binding/transfer activities.…”