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. Epub 2016 Sep 5.

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.

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Amino Acids / deficiency
  • Animals
  • Autophagy* / drug effects
  • Disease Models, Animal
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism
  • Peroxisomal Biogenesis Factor 2
  • Peroxisome-Targeting Signal 1 Receptor
  • Peroxisomes / drug effects
  • Peroxisomes / enzymology*
  • Peroxisomes / pathology
  • Protein-Energy Malnutrition / enzymology*
  • Protein-Energy Malnutrition / genetics
  • Protein-Energy Malnutrition / pathology
  • Proteins / metabolism
  • Proteolysis
  • RNA Interference
  • Rats
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Transfection
  • Ubiquitination

Substances

  • ABCD3 protein, human
  • ATP-Binding Cassette Transporters
  • Abcd3 protein, mouse
  • Amino Acids
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • NBR1 protein, human
  • PEX2 protein, human
  • PEX2 protein, mouse
  • PEX5 protein, human
  • Peroxisome-Targeting Signal 1 Receptor
  • Pex2 protein, rat
  • Pex5 protein, mouse
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Peroxisomal Biogenesis Factor 2
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Sirolimus

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