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PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation

Peroxisomes are metabolic organelles necessary for anabolic and catabolic lipid reactions whose numbers are highly dynamic based on the metabolic need of the cells. One mechanism to regulate peroxisome numbers is through an autophagic process called pexophagy. In mammalian cells, ubiquitination of p...

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Autores principales: Sargent, Graeme, van Zutphen, Tim, Shatseva, Tatiana, Zhang, Ling, Di Giovanni, Valeria, Bandsma, Robert, Kim, Peter Kijun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021090/
https://www.ncbi.nlm.nih.gov/pubmed/27597759
http://dx.doi.org/10.1083/jcb.201511034
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author Sargent, Graeme
van Zutphen, Tim
Shatseva, Tatiana
Zhang, Ling
Di Giovanni, Valeria
Bandsma, Robert
Kim, Peter Kijun
author_facet Sargent, Graeme
van Zutphen, Tim
Shatseva, Tatiana
Zhang, Ling
Di Giovanni, Valeria
Bandsma, Robert
Kim, Peter Kijun
author_sort Sargent, Graeme
collection PubMed
description Peroxisomes are metabolic organelles necessary for anabolic and catabolic lipid reactions whose numbers are highly dynamic based on the metabolic need of the cells. One mechanism to regulate peroxisome numbers is through an autophagic process called pexophagy. In mammalian cells, ubiquitination of peroxisomal membrane proteins signals pexophagy; however, the E3 ligase responsible for mediating ubiquitination is not known. Here, we report that the peroxisomal E3 ubiquitin ligase peroxin 2 (PEX2) is the causative agent for mammalian pexophagy. Expression of PEX2 leads to gross ubiquitination of peroxisomes and degradation of peroxisomes in an NBR1-dependent autophagic process. We identify PEX5 and PMP70 as substrates of PEX2 that are ubiquitinated during amino acid starvation. We also find that PEX2 expression is up-regulated during both amino acid starvation and rapamycin treatment, suggesting that the mTORC1 pathway regulates pexophagy by regulating PEX2 expression levels. Finally, we validate our findings in vivo using an animal model.
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spelling pubmed-50210902017-03-12 PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation Sargent, Graeme van Zutphen, Tim Shatseva, Tatiana Zhang, Ling Di Giovanni, Valeria Bandsma, Robert Kim, Peter Kijun J Cell Biol Research Articles Peroxisomes are metabolic organelles necessary for anabolic and catabolic lipid reactions whose numbers are highly dynamic based on the metabolic need of the cells. One mechanism to regulate peroxisome numbers is through an autophagic process called pexophagy. In mammalian cells, ubiquitination of peroxisomal membrane proteins signals pexophagy; however, the E3 ligase responsible for mediating ubiquitination is not known. Here, we report that the peroxisomal E3 ubiquitin ligase peroxin 2 (PEX2) is the causative agent for mammalian pexophagy. Expression of PEX2 leads to gross ubiquitination of peroxisomes and degradation of peroxisomes in an NBR1-dependent autophagic process. We identify PEX5 and PMP70 as substrates of PEX2 that are ubiquitinated during amino acid starvation. We also find that PEX2 expression is up-regulated during both amino acid starvation and rapamycin treatment, suggesting that the mTORC1 pathway regulates pexophagy by regulating PEX2 expression levels. Finally, we validate our findings in vivo using an animal model. The Rockefeller University Press 2016-09-12 /pmc/articles/PMC5021090/ /pubmed/27597759 http://dx.doi.org/10.1083/jcb.201511034 Text en © 2016 Sargent et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Sargent, Graeme
van Zutphen, Tim
Shatseva, Tatiana
Zhang, Ling
Di Giovanni, Valeria
Bandsma, Robert
Kim, Peter Kijun
PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation
title PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation
title_full PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation
title_fullStr PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation
title_full_unstemmed PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation
title_short PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation
title_sort pex2 is the e3 ubiquitin ligase required for pexophagy during starvation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021090/
https://www.ncbi.nlm.nih.gov/pubmed/27597759
http://dx.doi.org/10.1083/jcb.201511034
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