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Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation

Lipid droplets (LDs) are ubiquitous organelles that fulfill essential roles in response to metabolic cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER)...

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Autores principales: Teixeira, Vitor, Martins, Telma S., Prinz, William A., Costa, Vítor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396576/
https://www.ncbi.nlm.nih.gov/pubmed/34445723
http://dx.doi.org/10.3390/ijms22169017
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author Teixeira, Vitor
Martins, Telma S.
Prinz, William A.
Costa, Vítor
author_facet Teixeira, Vitor
Martins, Telma S.
Prinz, William A.
Costa, Vítor
author_sort Teixeira, Vitor
collection PubMed
description Lipid droplets (LDs) are ubiquitous organelles that fulfill essential roles in response to metabolic cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). However, our understanding of signaling networks, especially transcriptional mechanisms, regulating membrane biogenesis is very limited. Here, we show that the nutrient-sensing Target of Rapamycin Complex 1 (TORC1) regulates LD formation at a transcriptional level, by targeting DGA1 expression, in a Sit4-, Mks1-, and Sfp1-dependent manner. We show that cytosolic pH (pHc), co-regulated by the plasma membrane H+-ATPase Pma1 and the vacuolar ATPase (V-ATPase), acts as a second messenger, upstream of protein kinase A (PKA), to adjust the localization and activity of the major transcription factor repressor Opi1, which in turn controls the metabolic switch between phospholipid metabolism and lipid storage. Together, this work delineates hitherto unknown molecular mechanisms that couple nutrient availability and pHc to LD formation through a transcriptional circuit regulated by major signaling transduction pathways.
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spelling pubmed-83965762021-08-28 Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation Teixeira, Vitor Martins, Telma S. Prinz, William A. Costa, Vítor Int J Mol Sci Article Lipid droplets (LDs) are ubiquitous organelles that fulfill essential roles in response to metabolic cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). However, our understanding of signaling networks, especially transcriptional mechanisms, regulating membrane biogenesis is very limited. Here, we show that the nutrient-sensing Target of Rapamycin Complex 1 (TORC1) regulates LD formation at a transcriptional level, by targeting DGA1 expression, in a Sit4-, Mks1-, and Sfp1-dependent manner. We show that cytosolic pH (pHc), co-regulated by the plasma membrane H+-ATPase Pma1 and the vacuolar ATPase (V-ATPase), acts as a second messenger, upstream of protein kinase A (PKA), to adjust the localization and activity of the major transcription factor repressor Opi1, which in turn controls the metabolic switch between phospholipid metabolism and lipid storage. Together, this work delineates hitherto unknown molecular mechanisms that couple nutrient availability and pHc to LD formation through a transcriptional circuit regulated by major signaling transduction pathways. MDPI 2021-08-20 /pmc/articles/PMC8396576/ /pubmed/34445723 http://dx.doi.org/10.3390/ijms22169017 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Teixeira, Vitor
Martins, Telma S.
Prinz, William A.
Costa, Vítor
Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation
title Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation
title_full Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation
title_fullStr Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation
title_full_unstemmed Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation
title_short Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation
title_sort target of rapamycin complex 1 (torc1), protein kinase a (pka) and cytosolic ph regulate a transcriptional circuit for lipid droplet formation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396576/
https://www.ncbi.nlm.nih.gov/pubmed/34445723
http://dx.doi.org/10.3390/ijms22169017
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