Open AccessTMEM147 interacts with Lamin B Receptor, regulates its localization and levels, and affects cholesterol homeostasis
Author(s) -
Andri Christodoulou,
Giannis Maimaris,
Andri Makrigiorgi,
Evelina Charidemou,
Christian Lüchtenborg,
Antonis Ververis,
Renos Georgiou,
Carsten W. Lederer,
Christof Haffner,
Britta Brügger,
Niovi Santama
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.245357
Subject(s) - biology , endoplasmic reticulum , microbiology and biotechnology , lamin , gene silencing , sterol regulatory element binding protein , sterol , downregulation and upregulation , transmembrane domain , biochemistry , cholesterol , receptor , gene , nucleus
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 in heterochromatin organization, via its N-terminus, and cholesterol biosynthesis, via its sterol-reductase C-terminal domain. We show that TMEM147 physically interacts with LBR and the C-terminus of LBR is essential for their functional interaction. We find that TMEM147 also physically interacts with key sterol reductase DHCR7 in cholesterol biosynthesis. Similar to LBR, TMEM147 downregulation results in sharp decline of DHCR protein levels and co-ordinate transcriptional decrease of LBR and DHCR7 expression. Consistently, 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.