The COP9 signalosome mediates the Spt23 regulated fatty acid desaturation and ergosterol biosynthesis

Abhishek Sinha; Ran Israeli; Angela Cirigliano; Shalev Gihaz; Beny Trabelcy; Gerhard H. Braus; Yoram Gerchman; Ayelet Fishman; Rodolfo Negri; Teresa Rinaldi; Elah Pick

doi:10.1096/fj.201902487r

The COP9 signalosome mediates the Spt23 regulated fatty acid desaturation and ergosterol biosynthesis

Abhishek Sinha, Ran Israeli, Angela Cirigliano, Shalev Gihaz, Beny Trabelcy, Gerhard H. Braus, Yoram Gerchman, Ayelet Fishman, Rodolfo Negri, Teresa Rinaldi, Elah Pick

Faculty of Natural Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

The COP9 signalosome (CSN) is a conserved eukaryotic complex, essential for vitality in all multicellular organisms and critical for the turnover of key cellular proteins through catalytic and non-catalytic activities. Saccharomyces cerevisiae is a powerful model organism for studying fundamental aspects of the CSN complex, since it includes a conserved enzymatic core but lacks non-catalytic activities, probably explaining its non-essentiality for life. A previous transcriptomic analysis of an S. cerevisiae strain deleted in the CSN5/RRI1 gene, encoding to the CSN catalytic subunit, revealed a downregulation of genes involved in lipid metabolism. We now show that the S. cerevisiae CSN holocomplex is essential for cellular lipid homeostasis. Defects in CSN assembly or activity lead to decreased quantities of ergosterol and unsaturated fatty acids (UFA); vacuole defects; diminished lipid droplets (LDs) size; and to accumulation of endoplasmic reticulum (ER) stress. The molecular mechanism behind these findings depends on CSN involvement in upregulating mRNA expression of SPT23. Spt23 is a novel activator of lipid desaturation and ergosterol biosynthesis. Our data reveal for the first time a functional link between the CSN holocomplex and Spt23. Moreover, CSN-dependent upregulation of SPT23 transcription is necessary for the fine-tuning of lipid homeostasis and for cellular health.

Original language	English
Pages (from-to)	4870-4889
Number of pages	20
Journal	FASEB Journal
Volume	34
Issue number	4
DOIs	https://doi.org/10.1096/fj.201902487r
State	Published - 1 Apr 2020

Bibliographical note

Funding Information:
We would like to thank Maya Schuldiner and Michael Glickman for reagents and antibodies; Raymond J Deshaies, Teresa Zoladek, Hagai Abeliovich, and Tommer Ravid for plasmids and yeast strains. We would like to thank a lot to Teresa Zolodek and to Tommer Ravid for discussions and valuable comments prior to submission. This work was supported by the Israel Ministry of Science and Technology (MOST) – Italy Ministry of Foreign Affairs (MAE) [grant 3‐9022 to EP and TR]; Israel Science Foundation [grant no.162/17 for EP]; Fellowship by the Program of the Israeli Council for Higher Education (PBC) for AS.

Funding Information:
We would like to thank Maya Schuldiner and Michael Glickman for reagents and antibodies; Raymond J Deshaies, Teresa Zoladek, Hagai Abeliovich, and Tommer Ravid for plasmids and yeast strains. We would like to thank a lot to Teresa Zolodek and to Tommer Ravid for discussions and valuable comments prior to submission. This work was supported by the Israel Ministry of Science and Technology (MOST) – Italy Ministry of Foreign Affairs (MAE) [grant 3-9022 to EP and TR]; Israel Science Foundation [grant no.162/17 for EP]; Fellowship by the Program of the Israeli Council for Higher Education (PBC) for AS.

Publisher Copyright:
© 2020 University of Haifa. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.

Keywords

COP9 signalosome
Csn5
Ergosterol
NEDD8
Ole1
Rub1
S. cerevisiae
Spt23

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

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10.1096/fj.201902487r

Cite this

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title = "The COP9 signalosome mediates the Spt23 regulated fatty acid desaturation and ergosterol biosynthesis",

abstract = "The COP9 signalosome (CSN) is a conserved eukaryotic complex, essential for vitality in all multicellular organisms and critical for the turnover of key cellular proteins through catalytic and non-catalytic activities. Saccharomyces cerevisiae is a powerful model organism for studying fundamental aspects of the CSN complex, since it includes a conserved enzymatic core but lacks non-catalytic activities, probably explaining its non-essentiality for life. A previous transcriptomic analysis of an S. cerevisiae strain deleted in the CSN5/RRI1 gene, encoding to the CSN catalytic subunit, revealed a downregulation of genes involved in lipid metabolism. We now show that the S. cerevisiae CSN holocomplex is essential for cellular lipid homeostasis. Defects in CSN assembly or activity lead to decreased quantities of ergosterol and unsaturated fatty acids (UFA); vacuole defects; diminished lipid droplets (LDs) size; and to accumulation of endoplasmic reticulum (ER) stress. The molecular mechanism behind these findings depends on CSN involvement in upregulating mRNA expression of SPT23. Spt23 is a novel activator of lipid desaturation and ergosterol biosynthesis. Our data reveal for the first time a functional link between the CSN holocomplex and Spt23. Moreover, CSN-dependent upregulation of SPT23 transcription is necessary for the fine-tuning of lipid homeostasis and for cellular health.",

keywords = "COP9 signalosome, Csn5, Ergosterol, NEDD8, Ole1, Rub1, S. cerevisiae, Spt23",

author = "Abhishek Sinha and Ran Israeli and Angela Cirigliano and Shalev Gihaz and Beny Trabelcy and Braus, {Gerhard H.} and Yoram Gerchman and Ayelet Fishman and Rodolfo Negri and Teresa Rinaldi and Elah Pick",

note = "Funding Information: We would like to thank Maya Schuldiner and Michael Glickman for reagents and antibodies; Raymond J Deshaies, Teresa Zoladek, Hagai Abeliovich, and Tommer Ravid for plasmids and yeast strains. We would like to thank a lot to Teresa Zolodek and to Tommer Ravid for discussions and valuable comments prior to submission. This work was supported by the Israel Ministry of Science and Technology (MOST) – Italy Ministry of Foreign Affairs (MAE) [grant 3‐9022 to EP and TR]; Israel Science Foundation [grant no.162/17 for EP]; Fellowship by the Program of the Israeli Council for Higher Education (PBC) for AS. Funding Information: We would like to thank Maya Schuldiner and Michael Glickman for reagents and antibodies; Raymond J Deshaies, Teresa Zoladek, Hagai Abeliovich, and Tommer Ravid for plasmids and yeast strains. We would like to thank a lot to Teresa Zolodek and to Tommer Ravid for discussions and valuable comments prior to submission. This work was supported by the Israel Ministry of Science and Technology (MOST) – Italy Ministry of Foreign Affairs (MAE) [grant 3-9022 to EP and TR]; Israel Science Foundation [grant no.162/17 for EP]; Fellowship by the Program of the Israeli Council for Higher Education (PBC) for AS. Publisher Copyright: {\textcopyright} 2020 University of Haifa. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.",

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AU - Israeli, Ran

AU - Cirigliano, Angela

AU - Gihaz, Shalev

AU - Trabelcy, Beny

AU - Braus, Gerhard H.

AU - Gerchman, Yoram

AU - Fishman, Ayelet

AU - Negri, Rodolfo

AU - Rinaldi, Teresa

AU - Pick, Elah

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N2 - The COP9 signalosome (CSN) is a conserved eukaryotic complex, essential for vitality in all multicellular organisms and critical for the turnover of key cellular proteins through catalytic and non-catalytic activities. Saccharomyces cerevisiae is a powerful model organism for studying fundamental aspects of the CSN complex, since it includes a conserved enzymatic core but lacks non-catalytic activities, probably explaining its non-essentiality for life. A previous transcriptomic analysis of an S. cerevisiae strain deleted in the CSN5/RRI1 gene, encoding to the CSN catalytic subunit, revealed a downregulation of genes involved in lipid metabolism. We now show that the S. cerevisiae CSN holocomplex is essential for cellular lipid homeostasis. Defects in CSN assembly or activity lead to decreased quantities of ergosterol and unsaturated fatty acids (UFA); vacuole defects; diminished lipid droplets (LDs) size; and to accumulation of endoplasmic reticulum (ER) stress. The molecular mechanism behind these findings depends on CSN involvement in upregulating mRNA expression of SPT23. Spt23 is a novel activator of lipid desaturation and ergosterol biosynthesis. Our data reveal for the first time a functional link between the CSN holocomplex and Spt23. Moreover, CSN-dependent upregulation of SPT23 transcription is necessary for the fine-tuning of lipid homeostasis and for cellular health.

AB - The COP9 signalosome (CSN) is a conserved eukaryotic complex, essential for vitality in all multicellular organisms and critical for the turnover of key cellular proteins through catalytic and non-catalytic activities. Saccharomyces cerevisiae is a powerful model organism for studying fundamental aspects of the CSN complex, since it includes a conserved enzymatic core but lacks non-catalytic activities, probably explaining its non-essentiality for life. A previous transcriptomic analysis of an S. cerevisiae strain deleted in the CSN5/RRI1 gene, encoding to the CSN catalytic subunit, revealed a downregulation of genes involved in lipid metabolism. We now show that the S. cerevisiae CSN holocomplex is essential for cellular lipid homeostasis. Defects in CSN assembly or activity lead to decreased quantities of ergosterol and unsaturated fatty acids (UFA); vacuole defects; diminished lipid droplets (LDs) size; and to accumulation of endoplasmic reticulum (ER) stress. The molecular mechanism behind these findings depends on CSN involvement in upregulating mRNA expression of SPT23. Spt23 is a novel activator of lipid desaturation and ergosterol biosynthesis. Our data reveal for the first time a functional link between the CSN holocomplex and Spt23. Moreover, CSN-dependent upregulation of SPT23 transcription is necessary for the fine-tuning of lipid homeostasis and for cellular health.

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KW - Ergosterol

KW - NEDD8

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KW - Rub1

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The COP9 signalosome mediates the Spt23 regulated fatty acid desaturation and ergosterol biosynthesis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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