Kentala, Henriikka and Koponen, Annika and Vihinen, Helena and Pirhonen, Juho and Liebisch, Gerhard and Pataj, Zoltan and Kivela, Annukka and Li, Shiqian and Karhinen, Leena and Jaaskelainen, Eeva and Andrews, Robert and Merilainen, Leena and Matysik, Silke and Ikonen, Elina and Zhou, You and Jokitalo, Eija and Olkkonen, Vesa M. (2018) OSBP-related protein-2 (ORP2): a novel Akt effector that controls cellular energy metabolism. CELLULAR AND MOLECULAR LIFE SCIENCES, 75 (21). pp. 4041-4057. ISSN 1420-682X, 1420-9071
Full text not available from this repository. (Request a copy)Abstract
ORP2 is a ubiquitously expressed OSBP-related protein previously implicated in endoplasmic reticulum (ER)lipid droplet (LD) contacts, triacylglycerol (TG) metabolism, cholesterol transport, adrenocortical steroidogenesis, and actin-dependent cell dynamics. Here, we characterize the role of ORP2 in carbohydrate and lipid metabolism by employing ORP2-knockout (KO) hepatoma cells (HuH7) generated by CRISPR-Cas9 gene editing. The ORP2-KO and control HuH7 cells were subjected to RNA sequencing, analyses of Akt signaling, carbohydrate and TG metabolism, the extracellular acidification rate, and the lipidome, as well as to transmission electron microscopy. The loss of ORP2 resulted in a marked reduction of active phosphorylated Akt(Ser473) and its target Glycogen synthase kinase 3(Ser9), consistent with defective Akt signaling. ORP2 was found to form a physical complex with the key controllers of Akt activity, Cdc37, and Hsp90, and to co-localize with Cdc37 and active Akt(Ser473) at lamellipodial plasma membrane regions, in addition to the previously reported ER-LD localization. ORP2-KO reduced glucose uptake, glycogen synthesis, glycolysis, mRNA-encoding glycolytic enzymes, and SREBP-1 target gene expression, and led to defective TG synthesis and storage. ORP2-KO did not reduce but rather increased ER-LD contacts under basal culture conditions and interfered with their expansion upon fatty acid loading. Together with our recently published work (Kentala et al. in FASEB J 32:1281-1295, 2018), this study identifies ORP2 as a new regulatory nexus of Akt signaling, cellular energy metabolism, actin cytoskeletal function, cell migration, and proliferation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | OXYSTEROL-BINDING-PROTEIN; LIPID DROPLETS; PHOSPHATIDYLSERINE TRANSPORT; PLASMA-MEMBRANE; GLUCOSE-UPTAKE; ER; STEROL; KINASE; CHOLESTEROL; EXPRESSION; Akt signaling; CRISPR-Cas9; Glycolysis; OSBPL2; OSBP-related protein; Triacylglycerol |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Oct 2019 08:53 |
| Last Modified: | 10 Oct 2019 08:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13584 |
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