Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene
Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene
Cellular cholesterol metabolism is subject to tight regulation to maintain adequate levels of this central lipid molecule. Herein, the sterol-responsive Liver X Receptors (LXRs) play an important role owing to their ability to reduce cellular cholesterol load. In this context, identifying the full set of LXR-regulated genes will contribute to our understanding of their role in cholesterol metabolism. Using global transcriptional analysis we report here the identification of RNF145 as an LXR-regulated target gene. We demonstrate that RNF145 is regulated by LXRs in both human and mouse primary cells and cell lines, and in vivo in mice. Regulation of RNF145 by LXR depends on a functional LXR-element in its proximal promotor. Consistent with LXR-dependent regulation of Rnf145 we show that regulation is lost in macrophages and fibroblasts from Lxrαβ(-/-) mice, and also in vivo in livers of Lxrα(-/-) mice treated with the LXR synthetic ligand T0901317. RNF145 is closely related to RNF139/TRC8, an E3 ligase implicated in control of SREBP processing. However, silencing of RNF145 in HepG2 or HeLa cells does not impair SREBP1/2 processing and sterol-responsive gene expression in these cells. Similar to TRC8, we demonstrate that RNF145 is localized to the ER and that it possesses intrinsic E3 ubiquitin ligase activity. In summary, we report the identification of RNF145 as an ER-resident E3 ubiquitin ligase that is transcriptionally controlled by LXR.
Animals, Cell Line, Cholesterol/metabolism, Endoplasmic Reticulum/metabolism, Gene Expression Regulation, Humans, Hydrocarbons, Fluorinated/pharmacology, Liver/drug effects, Liver X Receptors/genetics, Membrane Proteins/genetics, Mice, Mice, Knockout, Promoter Regions, Genetic, Sulfonamides/pharmacology, Transcription, Genetic, Ubiquitin-Protein Ligases/metabolism, Ubiquitination
e0172721
Cook, Emma C.L.
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Nelson, Jessica K
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Sorrentino, Vincenzo
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Koenis, Duco
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Moeton, Martina
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Scheij, Saskia
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Ottenhoff, Roelof
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Bleijlevens, Boris
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Loregger, Anke
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Zelcer, Noam
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23 February 2017
Cook, Emma C.L.
4a22ced7-83cf-4c33-b028-0fc258e2b78f
Nelson, Jessica K
7dc3f0c8-5a67-4467-a332-efd560a0630b
Sorrentino, Vincenzo
f0cb3b5b-3a17-4ab3-ab65-180a7ee50d8a
Koenis, Duco
2fce0429-69b3-4175-8367-dcaa1156d236
Moeton, Martina
513f1f1d-59cd-45d9-8154-e2a676bd8c68
Scheij, Saskia
7863fcb2-eeba-43ab-93d5-8c9c08ad4289
Ottenhoff, Roelof
18e9d85a-7e89-4d67-9acd-015b503de1f0
Bleijlevens, Boris
9d48bf2e-1b43-4f9d-82b7-436705a9ce5d
Loregger, Anke
35d8c1fe-e11e-481e-bd35-e8160c079231
Zelcer, Noam
c5eff664-b107-4a7c-9823-11ccb8149fbc
Cook, Emma C.L., Nelson, Jessica K, Sorrentino, Vincenzo, Koenis, Duco, Moeton, Martina, Scheij, Saskia, Ottenhoff, Roelof, Bleijlevens, Boris, Loregger, Anke and Zelcer, Noam
(2017)
Identification of the ER-resident E3 ubiquitin ligase RNF145 as a novel LXR-regulated gene.
PLoS ONE, 12 (2), .
(doi:10.1371/journal.pone.0172721).
Abstract
Cellular cholesterol metabolism is subject to tight regulation to maintain adequate levels of this central lipid molecule. Herein, the sterol-responsive Liver X Receptors (LXRs) play an important role owing to their ability to reduce cellular cholesterol load. In this context, identifying the full set of LXR-regulated genes will contribute to our understanding of their role in cholesterol metabolism. Using global transcriptional analysis we report here the identification of RNF145 as an LXR-regulated target gene. We demonstrate that RNF145 is regulated by LXRs in both human and mouse primary cells and cell lines, and in vivo in mice. Regulation of RNF145 by LXR depends on a functional LXR-element in its proximal promotor. Consistent with LXR-dependent regulation of Rnf145 we show that regulation is lost in macrophages and fibroblasts from Lxrαβ(-/-) mice, and also in vivo in livers of Lxrα(-/-) mice treated with the LXR synthetic ligand T0901317. RNF145 is closely related to RNF139/TRC8, an E3 ligase implicated in control of SREBP processing. However, silencing of RNF145 in HepG2 or HeLa cells does not impair SREBP1/2 processing and sterol-responsive gene expression in these cells. Similar to TRC8, we demonstrate that RNF145 is localized to the ER and that it possesses intrinsic E3 ubiquitin ligase activity. In summary, we report the identification of RNF145 as an ER-resident E3 ubiquitin ligase that is transcriptionally controlled by LXR.
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Accepted/In Press date: 8 February 2017
Published date: 23 February 2017
Keywords:
Animals, Cell Line, Cholesterol/metabolism, Endoplasmic Reticulum/metabolism, Gene Expression Regulation, Humans, Hydrocarbons, Fluorinated/pharmacology, Liver/drug effects, Liver X Receptors/genetics, Membrane Proteins/genetics, Mice, Mice, Knockout, Promoter Regions, Genetic, Sulfonamides/pharmacology, Transcription, Genetic, Ubiquitin-Protein Ligases/metabolism, Ubiquitination
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Local EPrints ID: 505337
URI: http://eprints.soton.ac.uk/id/eprint/505337
ISSN: 1932-6203
PURE UUID: 5608610e-f1aa-494c-8626-8fcf6793f899
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Date deposited: 07 Oct 2025 16:37
Last modified: 08 Oct 2025 02:17
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Author:
Emma C.L. Cook
Author:
Jessica K Nelson
Author:
Vincenzo Sorrentino
Author:
Duco Koenis
Author:
Martina Moeton
Author:
Saskia Scheij
Author:
Roelof Ottenhoff
Author:
Boris Bleijlevens
Author:
Anke Loregger
Author:
Noam Zelcer
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