Affinage

PEX13

Peroxisomal membrane protein PEX13 · UniProt Q92968

Length
403 aa
Mass
44.1 kDa
Annotated
2026-04-29
31 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX13 is an integral peroxisomal membrane protein that serves as a central docking factor for peroxisomal matrix protein import and as a gatekeeper of organelle quality control through regulation of pexophagy. Its SH3 domain, which faces the peroxisome matrix in a Nout-Cin topology, binds WxxxF/Y motifs in the PTS1 receptor PEX5 via a non-canonical surface and interacts with PEX14 through both the SH3 domain and an intraperoxisomal site; an intramolecular FxxxF motif regulates PEX5 binding by competing for the same SH3 surface, and PEX13 homooligomerization at the membrane is additionally required for PTS1 import (PMID:38632234, PMID:23716570, PMID:15798189, PMID:30414318). Loss of PEX13 eliminates both PTS1- and PTS2-dependent import, abolishes peroxisomal fatty acid oxidation and plasmalogen synthesis, and causes Zellweger spectrum peroxisome biogenesis disorders; brain-specific deletion impairs cerebellar development with elevated ROS and mitochondrial dysfunction (PMID:12897163, PMID:10441568, PMID:20959636). PEX13 also prevents pexophagy of healthy peroxisomes by limiting ubiquitinated PEX5 accumulation and peroxisomal ROS—its downregulation during amino acid starvation facilitates pexophagy through an ATM–PINK1–STUB1–ABCD3–SQSTM1 cascade—and is independently required for selective autophagy of damaged mitochondria and viruses (PMID:36541703, PMID:41927977, PMID:27827795).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Identification of PEX13 as the gene mutated in a Zellweger spectrum complementation group established it as a peroxisomal membrane docking factor for PEX5, linking SH3 domain integrity to peroxisomal matrix protein import and human disease.

    Evidence Complementation cloning from PBD patient fibroblasts, missense/nonsense mutation analysis, temperature-sensitive rescue in CHO cells

    PMID:10332040 PMID:10441568

    Open questions at the time
    • Precise stoichiometry and architecture of the docking complex unknown
    • Whether PEX13 has import-independent functions not addressed
  2. 2003 High

    A knockout mouse model demonstrated that PEX13 is essential for both PTS1- and PTS2-dependent import in vivo, and that its loss abolishes peroxisomal fatty acid oxidation and plasmalogen synthesis, confirming it as non-redundant in the import machinery.

    Evidence Cre-mediated Pex13 knockout mouse with biochemical assays and immunofluorescence

    PMID:12897163

    Open questions at the time
    • Tissue-specific consequences not yet dissected
    • Contribution of individual PEX13 interaction interfaces to in vivo import not tested
  3. 2005 High

    Dissection of yeast Pex13–Pex14 interactions revealed two binding sites (SH3 domain and intraperoxisomal region) plus a Pex5-dependent contribution, showing that multiple simultaneous contacts are required for full docking complex assembly and import.

    Evidence Double/triple yeast mutant combinations with co-purification and oleic acid growth assays

    PMID:15798189

    Open questions at the time
    • Structural basis of the intraperoxisomal binding site unresolved
    • Whether the same dual-site architecture applies in mammals not shown
  4. 2010 High

    Brain-specific PEX13 deletion revealed that peroxisomal dysfunction causes cerebellar developmental defects, elevated ROS, and secondary mitochondrial dysfunction, establishing a cell-autonomous link between peroxisomal import and neuronal survival.

    Evidence Conditional brain Pex13 KO mouse with ROS measurement, mitochondrial assays, and histology

    PMID:20959636

    Open questions at the time
    • Which specific metabolites drive ROS elevation and mitochondrial damage not identified
    • Whether neuronal phenotype is import-dependent or involves PEX13's autophagy role unknown
  5. 2013 High

    Demonstration that PEX13 forms homooligomers at the peroxisomal membrane, mediated by the conserved W313 residue, and that this self-association is required for PTS1 import independently of PEX14 binding, revealed an additional layer of import regulation.

    Evidence Live-cell FRET, co-immunoprecipitation, W313G mutant complementation

    PMID:23716570

    Open questions at the time
    • Oligomeric stoichiometry and whether oligomerization forms part of the translocation channel unknown
    • Whether homooligomerization also affects PTS2 import not tested
  6. 2016 Medium

    Discovery that PEX13 is required for selective autophagy (virophagy and mitophagy) independently of general peroxisomal import expanded its functional repertoire beyond peroxisome biogenesis to organelle quality control.

    Evidence PEX13 KO/knockdown with mitophagy and Sindbis virophagy assays; disease mutants I326T and W313G specifically defective in mitophagy

    PMID:27827795

    Open questions at the time
    • Molecular mechanism by which PEX13 promotes mitophagy/virophagy undefined
    • Whether selective autophagy function is SH3-dependent or involves a distinct domain unknown
    • Single-lab finding not yet independently replicated
  7. 2018 High

    Determination of PEX13's Nout-Cin topology—with the SH3 domain facing the peroxisome matrix—resolved a longstanding controversy about import machinery organization and reframed how the docking complex is assembled across the membrane.

    Evidence Protease protection on reconstituted proteoliposomes and purified rat liver peroxisomes, mass spectrometry, Edman degradation

    PMID:30414318

    Open questions at the time
    • How cytoplasmic PEX5 accesses the intraperoxisomal SH3 domain during import not mechanistically explained
    • No full-length PEX13 structure available
  8. 2023 High

    Establishing that PEX13 actively prevents pexophagy of healthy peroxisomes by limiting ubiquitinated PEX5 accumulation and peroxisomal ROS—and that starvation-induced PEX13 downregulation triggers pexophagy—defined PEX13 as a molecular switch between peroxisome maintenance and turnover.

    Evidence CRISPR KO, quantitative fluorescence microscopy, zebrafish model, ubiquitination and ROS assays

    PMID:36541703

    Open questions at the time
    • Mechanism of starvation-induced PEX13 downregulation (transcriptional vs. post-translational) not fully resolved
    • Whether PEX13 directly deubiquitinates PEX5 or prevents ubiquitination upstream unknown
  9. 2024 High

    Crystal structures of the PEX13 SH3 domain revealed that PEX5 WxxxF/Y motifs bind a non-canonical surface distinct from classical PxxP recognition, and that an intramolecular FxxxF motif competes with PEX5 for this surface while also mediating PEX14 binding, providing a structural basis for regulated docking.

    Evidence X-ray crystallography, NMR, biochemical binding assays, mutagenesis, functional import assays

    PMID:38632234

    Open questions at the time
    • No structure of a full-length PEX13 or PEX13–PEX14–PEX5 ternary complex
    • How FxxxF autoinhibition is relieved during active import not defined
  10. 2025 Medium

    Identification of ZBTB17/MIZ1 as a direct transcriptional regulator of PEX13 connected ubiquitin ligase-dependent transcriptional control to peroxisomal import capacity and downstream purine metabolism.

    Evidence CRISPR/Cas9 ubiquitin ligase library screen, transcriptional reporter assays, siRNA knockdown, metabolomics

    PMID:40243840

    Open questions at the time
    • Whether ZBTB17 regulation of PEX13 is physiologically modulated in specific tissues unknown
    • Single-lab finding
  11. 2025 Medium

    PEDV NSP8 was shown to directly target PEX13 for autophagy-lysosomal degradation, triggering PEX5 ubiquitination and pexophagy that suppresses MAVS-dependent IFN-III signaling, revealing viral exploitation of PEX13's anti-pexophagy function for immune evasion.

    Evidence Mass spectrometry interaction screen, co-immunoprecipitation, autophagy inhibitors, IFN-III assays in PEDV-infected cells

    PMID:41186416

    Open questions at the time
    • Whether other viruses use the same PEX13-degradation strategy not examined
    • Structural basis of NSP8–PEX13 interaction unknown
    • Single-lab finding
  12. 2026 Medium

    The signaling cascade downstream of PEX13 loss during pexophagy was elucidated as ATM–PINK1–STUB1–ABCD3–SQSTM1, where PINK1 phosphorylation activates STUB1 E3 ligase activity toward ABCD3 to recruit SQSTM1, providing a complete molecular pathway for pexophagy initiation.

    Evidence siRNA screening, phosphorylation and ubiquitination assays, epistasis with ATM/PINK1 inhibitors and mutants

    PMID:41927977

    Open questions at the time
    • Whether this cascade operates in all cell types not tested
    • How ATM senses peroxisomal dysfunction upstream of PINK1 unclear
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full-length structure of PEX13, the mechanism by which its intraperoxisomal SH3 domain engages cytoplasmic PEX5 during translocation, and the molecular basis of its import-independent role in selective autophagy.
  • No full-length PEX13 structure or cryo-EM of the assembled import complex
  • Mechanism coupling FxxxF autoinhibition relief to cargo translocation unknown
  • Whether PEX13's autophagy function is separable from its import function at the domain level unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0060090 molecular adaptor activity 3
Localization
GO:0043226 organelle 4
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 5 R-HSA-9609507 Protein localization 4 R-HSA-9612973 Autophagy 4 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2
Partners
PEX14PEX3PEX5PINK1SQSTM1STUB1ZBTB17
Complex memberships
Peroxisomal docking/import complex (PEX13–PEX14–PEX5)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PEX13 encodes a peroxisomal membrane protein with a cytoplasmically exposed SH3 domain that functions as a docking factor for the PTS1 receptor PEX5; missense mutations in the SH3 domain reduce PEX13 activity and impair peroxisomal matrix protein import Complementation of PBD patient fibroblasts by PEX13 expression, missense mutation analysis, analogous yeast mutation validation American journal of human genetics High 10332040 10441568
1999 PEX13 SH3 domain temperature-sensitive mutation I326T renders the protein unstable at 37°C but stable at 30°C, and a nonsense mutation W234ter causing loss of SH3 domain and transmembrane domain leads to severe Zellweger phenotype, demonstrating domain-function relationships Patient mutation analysis, temperature-sensitive rescue assay in PEX13-defective CHO cells expressing mutant PEX13 cDNA Human molecular genetics High 10332040
2003 Pex13 knockout mice lack morphologically intact peroxisomes and show deficient import of matrix proteins containing either PTS1 or PTS2 signals, with severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis Conditional Cre-mediated knockout mouse, biochemical assays of peroxisomal fatty acid oxidation and plasmalogen synthesis, immunofluorescence for matrix protein import Molecular and cellular biology High 12897163
2005 Yeast Pex13 directly binds Pex14 via two sites: its SH3 domain and a novel intraperoxisomal site; Pex5 also contributes to Pex13-Pex14 association; all three interactions together are required for full PTS1- and PTS2-dependent matrix protein import and association of Pex13 with the docking complex Genetic epistasis with double/triple mutant combinations, co-purification assays, growth on oleic acid, in vivo import assays Molecular and cellular biology High 15798189
2013 Human PEX13 forms homooligomers at the peroxisomal membrane; the conserved W313 residue in the SH3 domain is required for self-association but not for PEX14 interaction; homooligomerization is necessary for PTS1 protein import; N-terminal half mediates peroxisomal localization which is prerequisite for homooligomerization Live-cell FRET microscopy, co-immunoprecipitation, truncation constructs, complementation rescue of import in W313G mutant cells Human molecular genetics High 23716570
2016 PEX13 is required for selective autophagy (virophagy of Sindbis virus and mitophagy of damaged mitochondria); disease-associated PEX13 mutants I326T and W313G are specifically defective in mitophagy; this function is shared with PEX3 but not PEX14 or PEX19 KO/knockdown cells with selective autophagy assays, disease-mutant expression, comparison across peroxin knockdowns EMBO reports Medium 27827795
2018 PEX13 adopts a Nout-Cin membrane topology, with its C-terminal SH3 domain exposed to the peroxisome matrix (intraperoxisomal), while PEX14 has Nin-Cout topology; this resolves the organization of the peroxisomal protein import machinery Protease-protection assays on proteoliposomes and purified rat liver peroxisomes, mass spectrometry, Edman degradation, western blotting with domain-specific antibodies The FEBS journal High 30414318
2023 PEX13 prevents pexophagy of healthy peroxisomes; loss of PEX13 causes accumulation of ubiquitinated PEX5 on peroxisomes and increased peroxisome-derived ROS, together inducing pexophagy; PEX13 protein levels are downregulated during amino acid starvation to facilitate pexophagy CRISPR gene editing, quantitative fluorescence microscopy, zebrafish model, ubiquitination assays, ROS measurement Autophagy High 36541703
2024 The C-terminal SH3 domain of PEX13 binds WxxxF/Y motifs in the import receptor PEX5; this is regulated by an intramolecular FxxxF motif proximal to the SH3 domain that competes with PEX5 binding; the FxxxF motif also mediates PEX14 binding; crystal structures reveal recognition through a non-canonical surface on the SH3 domain distinct from canonical PxxP-binding surface Biochemical binding assays, NMR, crystal structures, mutagenesis, functional import assays Nature communications High 38632234
2025 ZBTB17/MIZ1 transcription factor directly regulates PEX13 expression to modulate peroxisomal matrix protein import; knockdown of ZBTB17 or PEX13 produces similar metabolic alterations including downregulated purine synthesis CRISPR/Cas9 ubiquitin ligase library screen, transcriptional reporter assays, siRNA knockdown, metabolomic profiling The Journal of cell biology Medium 40243840
2025 PEDV nonstructural protein NSP8 directly interacts with PEX13 (identified by mass spectrometry) and induces its degradation via the autophagy-lysosomal pathway, leading to ubiquitination of PEX5, NBR1 recruitment, and pexophagy, thereby suppressing MAVS-dependent IFN-III production Mass spectrometry interaction screen, co-immunoprecipitation, autophagy pathway inhibitors, IFN-III production assays mBio Medium 41186416
2026 PEX13 depletion-induced pexophagy is orchestrated by an ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade; PINK1 phosphorylates STUB1 to enhance its E3 ligase activity toward ABCD3, which recruits SQSTM1 for peroxisomal degradation siRNA screening, phosphorylation assays, ubiquitination assays, epistasis with ATM and PINK1 inhibitors/mutants Cell death and differentiation Medium 41927977
2010 Brain-restricted PEX13 deficiency in mice leads to impaired cerebellar development, defective granule cell migration, and Purkinje cell layer development; cultured PEX13-null cerebellar neurons exhibit elevated reactive oxygen species, increased mitochondrial SOD2, enhanced apoptosis, and mitochondrial dysfunction Conditional brain-specific Cex13 knockout mouse, ROS measurements, mitochondrial function assays, histology Disease models & mechanisms High 20959636
2020 Hepatocyte-specific deletion of Pex13 reduces hepatic hepcidin expression through increased SMAD7 signaling and ER stress, disrupting systemic iron homeostasis Conditional hepatocyte Pex13 KO mouse, siRNA knockdown in HepG2/C3A cells, hepcidin and SMAD7 expression analysis Biochimica et biophysica acta. Molecular basis of disease Medium 32565019

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. Molecular and cellular biology 92 12897163
1999 Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders. Human molecular genetics 70 10332040
2006 The Arabidopsis pex12 and pex13 mutants are defective in both PTS1- and PTS2-dependent protein transport to peroxisomes. The Plant journal : for cell and molecular biology 68 16813573
1999 PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis disorders. American journal of human genetics 56 10441568
2010 PEX13 deficiency in mouse brain as a model of Zellweger syndrome: abnormal cerebellum formation, reactive gliosis and oxidative stress. Disease models & mechanisms 54 20959636
2023 PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS. Autophagy 49 36541703
2010 Peroxisome biogenesis factor PEX13 is required for appressorium-mediated plant infection by the anthracnose fungus Colletotrichum orbiculare. Molecular plant-microbe interactions : MPMI 41 20192831
2005 Identification of a novel, intraperoxisomal pex14-binding site in pex13: association of pex13 with the docking complex is essential for peroxisomal matrix protein import. Molecular and cellular biology 41 15798189
2016 Peroxisomal protein PEX13 functions in selective autophagy. EMBO reports 40 27827795
2006 Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients. Human mutation 39 17041890
2018 Membrane topologies of PEX13 and PEX14 provide new insights on the mechanism of protein import into peroxisomes. The FEBS journal 38 30414318
1999 Isolation, characterization and mutation analysis of PEX13-defective Chinese hamster ovary cell mutants. Human molecular genetics 34 10441330
2010 Reducing PEX13 expression ameliorates physiological defects of late-acting peroxin mutants. Traffic (Copenhagen, Denmark) 30 20969679
2019 Pex13 and Pex14, the key components of the peroxisomal docking complex, are required for peroxisome formation, host infection and pathogenicity-related morphogenesis in Magnaporthe oryzae. Virulence 29 30905264
2013 Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis. Human molecular genetics 25 23716570
2012 Trypanosomes contain two highly different isoforms of peroxin PEX13 involved in glycosome biogenesis. FEBS letters 23 22641036
2014 A viable Arabidopsis pex13 missense allele confers severe peroxisomal defects and decreases PEX5 association with peroxisomes. Plant molecular biology 22 25008153
2009 Zellweger syndrome caused by PEX13 deficiency: report of two novel mutations. American journal of medical genetics. Part A 15 19449432
1998 Genomic structure of PEX13, a candidate peroxisome biogenesis disorder gene. Genomics 13 9878256
2021 PEX13 is required for thermogenesis of white adipose tissue in cold-exposed mice. Biochimica et biophysica acta. Molecular and cell biology of lipids 11 34517131
2024 Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif. Nature communications 10 38632234
2020 Trypanosoma brucei Pex13.2 Is an Accessory Peroxin That Functions in the Import of Peroxisome Targeting Sequence Type 2 Proteins and Localizes to Subdomains of the Glycosome. mSphere 10 32075879
2002 Pex13, the mouse ortholog of the human peroxisome biogenesis disorder PEX13 gene: gene structure, tissue expression, and localization of the protein to peroxisomes. Genomics 8 11829486
2020 Hepatocyte-specific deletion of peroxisomal protein PEX13 results in disrupted iron homeostasis. Biochimica et biophysica acta. Molecular basis of disease 4 32565019
2017 Impaired neurogenesis and associated gliosis in mouse brain with PEX13 deficiency. Molecular and cellular neurosciences 4 29187321
2009 Quantitative genotyping of mouse brain-specific PEX13 gene disruption by real-time PCR. Journal of neuroscience methods 3 19422853
2023 Severe Zellweger spectrum disorder due to a novel missense variant in the PEX13 gene: A case report and the literature review. Molecular genetics & genomic medicine 1 37962062
2026 Loss of Peroxisomal Membrane Proteins PEX13 and PEX14 Disrupts Fatty Acid Oxidation and Drives Lipid Imbalance. Bioscience reports 0 41860470
2026 PINK1 and STUB1 pathway orchestrates peroxisomal selective autophagy by PEX13 depletion. Cell death and differentiation 0 41927977
2025 ZBTB17/MIZ1 promotes peroxisome biogenesis by transcriptional regulation of PEX13. The Journal of cell biology 0 40243840
2025 PEDV NSP8 inhibits IFN-III production induced by MAVS through downregulation of PEX13. mBio 0 41186416