TMEM147 interacts with lamin B receptor, regulates its localization and levels, and affects cholesterol homeostasis

• Verfasst von: Christodoulou, Andri [VerfasserIn]
• Verfasst von: Maimaris, Giannis [VerfasserIn]
• Verfasst von: Makrigiorgi, Andri [VerfasserIn]
• Verfasst von: Charidemou, Evelina [VerfasserIn]
• Verfasst von: Lüchtenborg, Christian [VerfasserIn]
• Verfasst von: Ververis, Antonis [VerfasserIn]
• Verfasst von: Georgiou, Renos [VerfasserIn]
• Verfasst von: Lederer, Carsten W. [VerfasserIn]
• Verfasst von: Haffner, Christof [VerfasserIn]
• Verfasst von: Brügger, Britta [VerfasserIn]
• Verfasst von: Santama, Niovi [VerfasserIn]
• Titel: TMEM147 interacts with lamin B receptor, regulates its localization and levels, and affects cholesterol homeostasis
• Verf.angabe: Andri Christodoulou, Giannis Maimaris, Andri Makrigiorgi, Evelina Charidemou, Christian Lüchtenborg, Antonis Ververis, Renos Georgiou, Carsten W. Lederer, Christof Haffner, Britta Brügger and Niovi Santama
• E-Jahr: 2020
• Jahr: 21 August 2020
• Umfang: 15 S.
• Teil: volume:133
• Teil: year:2020
• Teil: number:16
• Teil: elocationid:245357
• Teil: pages:1-15
• Teil: extent:15
• Fussnoten: Gesehen am 10.06.2021 ; DOI funktioniert nicht
• Titel Quelle: Enthalten in: Journal of cell science
• Ort Quelle: Cambridge : Company of Biologists Limited, 1853
• Jahr Quelle: 2020
• Band/Heft Quelle: 133(2020), 16, Artikel-ID 245357, Seite 1-15
• ISSN Quelle: 1477-9137
• DOI: doi:10.1242/jcs.245357
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1760242012

Abstract

The structurally and functionally complex endoplasmic reticulum (ER) hosts critical processes including lipid synthesis. Here, we focus on the functional characterization of transmembrane protein TMEM147, and report that it localizes at the ER and nuclear envelope in HeLa cells. Silencing of TMEM147 drastically reduces the level of lamin B receptor (LBR) at the inner nuclear membrane and results in mistargeting of LBR to the ER. LBR possesses a modular structure and corresponding bifunctionality, acting in heterochromatin organization via its N-terminus and in cholesterol biosynthesis via its sterol-reductase C-terminal domain. We show that TMEM147 physically interacts with LBR, and that the C-terminus of LBR is essential for their functional interaction. We find that TMEM147 also physically interacts with the key sterol reductase DHCR7, which is involved in cholesterol biosynthesis. Similar to what was seen for LBR, TMEM147 downregulation results in a sharp decline of DHCR protein levels and co-ordinate transcriptional decreases of LBR and DHCR7 expression. Consistent with this, lipidomic analysis upon TMEM147 silencing identified changes in cellular cholesterol levels, cholesteryl ester levels and profile, and in cellular cholesterol uptake, raising the possibility that TMEM147 is an important new regulator of cholesterol homeostasis in cells.This article has an associated First Person interview with the first author of the paper.