OSBP-related protein-2 (ORP2) : a novel Akt effector that controls cellular energy metabolism

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Kentala , H , Koponen , A , Vihinen , H , Pirhonen , J , Liebisch , G , Pataj , Z , Kivelä , A , Li , S , Karhinen , L , Jääskeläinen , E , Andrews , R , Meriläinen , L , Matysik , S , Ikonen , E , Zhou , Y , Jokitalo , E & Olkkonen , V M 2018 , ' OSBP-related protein-2 (ORP2) : a novel Akt effector that controls cellular energy metabolism ' , Cellular and Molecular Life Sciences , vol. 75 , no. 21 , pp. 4041-4057 . https://doi.org/10.1007/s00018-018-2850-8

Title: OSBP-related protein-2 (ORP2) : a novel Akt effector that controls cellular energy metabolism
Author: Kentala, Henriikka; Koponen, Annika; Vihinen, Helena; Pirhonen, Juho; Liebisch, Gerhard; Pataj, Zoltan; Kivelä, Annukka; Li, Shiqian; Karhinen, Leena; Jääskeläinen, Eeva; Andrews, Robert; Meriläinen, Leena; Matysik, Silke; Ikonen, Elina; Zhou, You; Jokitalo, Eija; Olkkonen, Vesa M.
Contributor organization: Institute of Biotechnology
Electron Microscopy
University of Helsinki
Department of Anatomy
Faculty of Medicine
Research Services
Lipid Trafficking Lab
Date: 2018-11
Language: eng
Number of pages: 17
Belongs to series: Cellular and Molecular Life Sciences
ISSN: 1420-682X
DOI: https://doi.org/10.1007/s00018-018-2850-8
URI: http://hdl.handle.net/10138/250548
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.
Subject: Akt signaling
OSBP-related protein
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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