The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders

Kelsey B. Law, Dana Bronte-Tinkew, Erminia Di Pietro, Ann Snowden, Richard O. Jones, Ann Moser, John H. Brumell, Nancy Braverman, Peter K. Kim

Research output: Contribution to journalArticle

Abstract

Peroxisome biogenesis disorders (PBDs) are metabolic disorders caused by the loss of peroxisomes. The majority of PBDs result from mutation in one of 3 genes that encode for the peroxisomal AAA ATPase complex (AAA-complex) required for cycling PEX5 for peroxisomal matrix protein import. Mutations in these genes are thought to result in a defect in peroxisome assembly by preventing the import of matrix proteins. However, we show here that loss of the AAA-complex does not prevent matrix protein import, but instead causes an upregulation of peroxisome degradation by macroautophagy, or pexophagy. The loss of AAA-complex function in cells results in the accumulation of ubiquitinated PEX5 on the peroxisomal membrane that signals pexophagy. Inhibiting autophagy by genetic or pharmacological approaches rescues peroxisome number, protein import and function. Our findings suggest that the peroxisomal AAA-complex is required for peroxisome quality control, whereas its absence results in the selective degradation of the peroxisome. Thus the loss of peroxisomes in PBD patients with mutations in their peroxisomal AAA-complex is a result of increased pexophagy. Our study also provides a framework for the development of novel therapeutic treatments for PBDs.

Original languageEnglish (US)
Pages (from-to)868-884
Number of pages17
JournalAutophagy
Volume13
Issue number5
DOIs
StatePublished - May 4 2017

Fingerprint

Peroxisomes
Biogenesis
Adenosine Triphosphatases
Proteins
Mutation
Genes
Autophagy
Quality Control
Up-Regulation
Pharmacology
Membranes

Keywords

  • AAA ATPase complex
  • autophagy
  • peroxisome biogenesis disorder
  • peroxisomes
  • PEX1
  • PEX26
  • PEX5
  • pexophagy
  • selective autophagy
  • Zellweger spectrum disorder

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders. / Law, Kelsey B.; Bronte-Tinkew, Dana; Di Pietro, Erminia; Snowden, Ann; Jones, Richard O.; Moser, Ann; Brumell, John H.; Braverman, Nancy; Kim, Peter K.

In: Autophagy, Vol. 13, No. 5, 04.05.2017, p. 868-884.

Research output: Contribution to journalArticle

Law, KB, Bronte-Tinkew, D, Di Pietro, E, Snowden, A, Jones, RO, Moser, A, Brumell, JH, Braverman, N & Kim, PK 2017, 'The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders' Autophagy, vol 13, no. 5, pp. 868-884. DOI: 10.1080/15548627.2017.1291470

Law, Kelsey B.; Bronte-Tinkew, Dana; Di Pietro, Erminia; Snowden, Ann; Jones, Richard O.; Moser, Ann; Brumell, John H.; Braverman, Nancy; Kim, Peter K. / The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders.

In: Autophagy, Vol. 13, No. 5, 04.05.2017, p. 868-884.

Research output: Contribution to journalArticle

@article{b3d2006316a348a0b1033f5d2b3fcbd5,
title = "The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders",
abstract = "Peroxisome biogenesis disorders (PBDs) are metabolic disorders caused by the loss of peroxisomes. The majority of PBDs result from mutation in one of 3 genes that encode for the peroxisomal AAA ATPase complex (AAA-complex) required for cycling PEX5 for peroxisomal matrix protein import. Mutations in these genes are thought to result in a defect in peroxisome assembly by preventing the import of matrix proteins. However, we show here that loss of the AAA-complex does not prevent matrix protein import, but instead causes an upregulation of peroxisome degradation by macroautophagy, or pexophagy. The loss of AAA-complex function in cells results in the accumulation of ubiquitinated PEX5 on the peroxisomal membrane that signals pexophagy. Inhibiting autophagy by genetic or pharmacological approaches rescues peroxisome number, protein import and function. Our findings suggest that the peroxisomal AAA-complex is required for peroxisome quality control, whereas its absence results in the selective degradation of the peroxisome. Thus the loss of peroxisomes in PBD patients with mutations in their peroxisomal AAA-complex is a result of increased pexophagy. Our study also provides a framework for the development of novel therapeutic treatments for PBDs.",
keywords = "AAA ATPase complex, autophagy, peroxisome biogenesis disorder, peroxisomes, PEX1, PEX26, PEX5, pexophagy, selective autophagy, Zellweger spectrum disorder",
author = "Law, {Kelsey B.} and Dana Bronte-Tinkew and {Di Pietro}, Erminia and Ann Snowden and Jones, {Richard O.} and Ann Moser and Brumell, {John H.} and Nancy Braverman and Kim, {Peter K.}",
year = "2017",
month = "5",
doi = "10.1080/15548627.2017.1291470",
volume = "13",
pages = "868--884",
journal = "Autophagy",
issn = "1554-8627",
publisher = "Landes Bioscience",
number = "5",

}

TY - JOUR

T1 - The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders

AU - Law,Kelsey B.

AU - Bronte-Tinkew,Dana

AU - Di Pietro,Erminia

AU - Snowden,Ann

AU - Jones,Richard O.

AU - Moser,Ann

AU - Brumell,John H.

AU - Braverman,Nancy

AU - Kim,Peter K.

PY - 2017/5/4

Y1 - 2017/5/4

N2 - Peroxisome biogenesis disorders (PBDs) are metabolic disorders caused by the loss of peroxisomes. The majority of PBDs result from mutation in one of 3 genes that encode for the peroxisomal AAA ATPase complex (AAA-complex) required for cycling PEX5 for peroxisomal matrix protein import. Mutations in these genes are thought to result in a defect in peroxisome assembly by preventing the import of matrix proteins. However, we show here that loss of the AAA-complex does not prevent matrix protein import, but instead causes an upregulation of peroxisome degradation by macroautophagy, or pexophagy. The loss of AAA-complex function in cells results in the accumulation of ubiquitinated PEX5 on the peroxisomal membrane that signals pexophagy. Inhibiting autophagy by genetic or pharmacological approaches rescues peroxisome number, protein import and function. Our findings suggest that the peroxisomal AAA-complex is required for peroxisome quality control, whereas its absence results in the selective degradation of the peroxisome. Thus the loss of peroxisomes in PBD patients with mutations in their peroxisomal AAA-complex is a result of increased pexophagy. Our study also provides a framework for the development of novel therapeutic treatments for PBDs.

AB - Peroxisome biogenesis disorders (PBDs) are metabolic disorders caused by the loss of peroxisomes. The majority of PBDs result from mutation in one of 3 genes that encode for the peroxisomal AAA ATPase complex (AAA-complex) required for cycling PEX5 for peroxisomal matrix protein import. Mutations in these genes are thought to result in a defect in peroxisome assembly by preventing the import of matrix proteins. However, we show here that loss of the AAA-complex does not prevent matrix protein import, but instead causes an upregulation of peroxisome degradation by macroautophagy, or pexophagy. The loss of AAA-complex function in cells results in the accumulation of ubiquitinated PEX5 on the peroxisomal membrane that signals pexophagy. Inhibiting autophagy by genetic or pharmacological approaches rescues peroxisome number, protein import and function. Our findings suggest that the peroxisomal AAA-complex is required for peroxisome quality control, whereas its absence results in the selective degradation of the peroxisome. Thus the loss of peroxisomes in PBD patients with mutations in their peroxisomal AAA-complex is a result of increased pexophagy. Our study also provides a framework for the development of novel therapeutic treatments for PBDs.

KW - AAA ATPase complex

KW - autophagy

KW - peroxisome biogenesis disorder

KW - peroxisomes

KW - PEX1

KW - PEX26

KW - PEX5

KW - pexophagy

KW - selective autophagy

KW - Zellweger spectrum disorder

UR - http://www.scopus.com/inward/record.url?scp=85019611162&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019611162&partnerID=8YFLogxK

U2 - 10.1080/15548627.2017.1291470

DO - 10.1080/15548627.2017.1291470

M3 - Article

VL - 13

SP - 868

EP - 884

JO - Autophagy

T2 - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 5

ER -