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Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation

The changing accessibility of nutrient resources induces the reprogramming of cellular metabolism in order to adapt the cell to the altered growth conditions. The nutrient-depending signaling depends on the kinases mTOR (mechanistic target of rapamycin), which is mainly activated by nitrogen-resourc...

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Autores principales: Boutouja, Fahd, Platta, Harald W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696409/
https://www.ncbi.nlm.nih.gov/pubmed/33202661
http://dx.doi.org/10.3390/biom10111553
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author Boutouja, Fahd
Platta, Harald W.
author_facet Boutouja, Fahd
Platta, Harald W.
author_sort Boutouja, Fahd
collection PubMed
description The changing accessibility of nutrient resources induces the reprogramming of cellular metabolism in order to adapt the cell to the altered growth conditions. The nutrient-depending signaling depends on the kinases mTOR (mechanistic target of rapamycin), which is mainly activated by nitrogen-resources, and PKA (protein kinase A), which is mainly activated by glucose, as well as both of their associated factors. These systems promote protein synthesis and cell proliferation, while they inhibit degradation of cellular content by unselective bulk autophagy. Much less is known about their role in selective autophagy pathways, which have a more regulated cellular function. Especially, we were interested to analyse the central Ras2-module of the PKA-pathway in the context of peroxisome degradation. Yeast Ras2 is homologous to the mammalian Ras proteins, whose mutant forms are responsible for 33% of human cancers. In the present study, we were able to demonstrate a context-dependent role of Ras2 activity depending on the type of mTOR-inhibition and glucose-sensing situation. When mTOR was inhibited directly via the macrolide rapamycin, peroxisome degradation was still partially suppressed by Ras2, while inactivation of Ras2 resulted in an enhanced degradation of peroxisomes, suggesting a role of Ras2 in the inhibition of peroxisome degradation in glucose-grown cells. In contrast, the inhibition of mTOR by shifting cells from oleate-medium, which lacks glucose, to pexophagy-medium, which contains glucose and is limited in nitrogen, required Ras2-activity for efficient pexophagy, strongly suggesting that the role of Ras2 in glucose sensing-associated signaling is more important in this context than its co-function in mTOR-related autophagy-inhibition.
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spelling pubmed-76964092020-11-29 Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation Boutouja, Fahd Platta, Harald W. Biomolecules Communication The changing accessibility of nutrient resources induces the reprogramming of cellular metabolism in order to adapt the cell to the altered growth conditions. The nutrient-depending signaling depends on the kinases mTOR (mechanistic target of rapamycin), which is mainly activated by nitrogen-resources, and PKA (protein kinase A), which is mainly activated by glucose, as well as both of their associated factors. These systems promote protein synthesis and cell proliferation, while they inhibit degradation of cellular content by unselective bulk autophagy. Much less is known about their role in selective autophagy pathways, which have a more regulated cellular function. Especially, we were interested to analyse the central Ras2-module of the PKA-pathway in the context of peroxisome degradation. Yeast Ras2 is homologous to the mammalian Ras proteins, whose mutant forms are responsible for 33% of human cancers. In the present study, we were able to demonstrate a context-dependent role of Ras2 activity depending on the type of mTOR-inhibition and glucose-sensing situation. When mTOR was inhibited directly via the macrolide rapamycin, peroxisome degradation was still partially suppressed by Ras2, while inactivation of Ras2 resulted in an enhanced degradation of peroxisomes, suggesting a role of Ras2 in the inhibition of peroxisome degradation in glucose-grown cells. In contrast, the inhibition of mTOR by shifting cells from oleate-medium, which lacks glucose, to pexophagy-medium, which contains glucose and is limited in nitrogen, required Ras2-activity for efficient pexophagy, strongly suggesting that the role of Ras2 in glucose sensing-associated signaling is more important in this context than its co-function in mTOR-related autophagy-inhibition. MDPI 2020-11-14 /pmc/articles/PMC7696409/ /pubmed/33202661 http://dx.doi.org/10.3390/biom10111553 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Boutouja, Fahd
Platta, Harald W.
Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation
title Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation
title_full Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation
title_fullStr Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation
title_full_unstemmed Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation
title_short Autophagy Stimulus-Dependent Role of the Small GTPase Ras2 in Peroxisome Degradation
title_sort autophagy stimulus-dependent role of the small gtpase ras2 in peroxisome degradation
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696409/
https://www.ncbi.nlm.nih.gov/pubmed/33202661
http://dx.doi.org/10.3390/biom10111553
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