2. Academic Validation
  3. PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation

PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation

  • J Cell Biol. 2016 Sep 12;214(6):677-90. doi: 10.1083/jcb.201511034.
Graeme Sargent 1,  Tim van Zutphen 2,  Tatiana Shatseva 3,  Ling Zhang 4,  Valeria Di Giovanni 4,  Robert Bandsma 5,  Peter Kijun Kim 1
Affiliations

Affiliations

  • 1 Cell Biology Department, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 2 Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9700 AD Groningen, Netherlands.
  • 3 Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 4 Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • 5 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada pkim@sickkids.ca robert.bandsma@sickkids.ca.
PMID: 27597759 DOI: 10.1083/jcb.201511034
Abstract

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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