Peroxisomal protein PEX13 functions in selective autophagy.
PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease-associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13-mediated mitophagy may contribute to ZSS pathogenesis.
Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Ming Y
MY
Lee
Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Rhea
R
Sumpter
Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Zhongju
Z
Zou
Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Shyam
S
Sirasanagandla
Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Yongjie
Y
Wei
Children's Medical Center Research Institute at the University of Texas Southwestern Medical Center, Dallas, TX, USA.
Prashant
P
Mishra
Department of Pediatrics and Pediatric Neurology, Georg August University, Göttingen, Germany.
Hendrik
H
Rosewich
Eskitis Institute for Drug Discovery and School of Natural Sciences Griffith University, Nathan, Qld, Australia.
Denis I
DI
Crane
Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA beth.levine@utsouthwestern.edu.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Beth
0000-0002-1460-1638
B
Levine
D000818:Animals; D001343:Autophagy; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D020675:Peroxisomes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D012845:Sindbis Virus / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015211:Zellweger Syndrome / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; C101884:PEX13 protein, human; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
PEX13; Zellweger syndrome; autophagy; mitophagy; virophagy