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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)...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8396576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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