Affinage

PEX13

Peroxisomal membrane protein PEX13 · UniProt Q92968

Length
403 aa
Mass
44.1 kDa
Annotated
2026-06-10
29 papers in source corpus 15 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX13 is an integral peroxisomal membrane protein that serves as a core docking factor of the peroxisomal protein import machinery, required for import of both PTS1- and PTS2-targeted matrix proteins (PMID:10441568, PMID:10332040, PMID:10441330, PMID:12897163). It adopts a Nout–Cin topology that places its C-terminal SH3 domain inside the peroxisomal matrix rather than facing the cytoplasm (PMID:30414318), where the SH3 domain engages intramolecularly with a proximal FxxxF motif and, through a non-canonical surface, recognizes PEX5 WxxxF/Y motifs; the same FxxxF motif mediates binding to PEX14 (PMID:38632234). PEX13 contacts PEX14 through two distinct sites—its SH3 domain and a separate intraperoxisomal site—with PEX5 also contributing to the assembly, and these interactions are differentially required for PTS1 versus PTS2 import (PMID:15798189). Human PEX13 homooligomerizes at the membrane via the conserved W313 residue, an interaction specifically required for PTS1 import (PMID:23716570). Loss of PEX13 abolishes intact peroxisome assembly and recapitulates Zellweger syndrome, with neonatal lethality, impaired fatty acid β-oxidation and plasmalogen synthesis in mouse models, and disease-causing SH3-domain missense mutations in patients (PMID:10441568, PMID:10332040, PMID:10441330, PMID:12897163). Beyond import, PEX13 restrains pexophagy by limiting accumulation of ubiquitinated PEX5 and peroxisomal ROS (PMID:36541703), and its loss activates an ATM–PINK1–STUB1–ABCD3–SQSTM1 cascade that drives selective peroxisome degradation (PMID:41927977); PEX13 is also required for selective autophagy including mitophagy and virophagy, functions disrupted by the disease mutants I326T and W313G (PMID:27827795). PEX13 expression is controlled transcriptionally by ZBTB17/MIZ1 (PMID:40243840), and viral hijacking of PEX13 degradation suppresses MAVS-dependent interferon signaling (PMID:41186416).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Established PEX13 as a peroxisomal membrane docking factor for the PTS1 receptor PEX5 and linked it causally to a human peroxisome biogenesis disorder.

    Evidence Complementation rescue in patient fibroblasts and CHO mutants with SH3-domain mutagenesis and cell-fusion complementation grouping

    PMID:10332040 PMID:10441330 PMID:10441568

    Open questions at the time
    • Did not resolve membrane topology of the SH3 domain
    • Did not define how PEX13 distinguishes PTS1 from PTS2 cargo
  2. 1999 Medium

    Showed that an SH3-domain missense mutation acts via protein destabilization, explaining temperature-sensitive import failure.

    Evidence Expression of I326T mutant cDNA in PEX13-defective CHO cells at permissive vs restrictive temperatures with RT-PCR mutation analysis

    PMID:10332040

    Open questions at the time
    • Single-lab temperature-shift assay
    • Did not determine structural basis of destabilization
  3. 2003 High

    Demonstrated in vivo that PEX13 is essential for assembly of intact peroxisomes and import of both PTS1 and PTS2 matrix proteins, defining the organismal consequences of its loss.

    Evidence Ubiquitous Cre/loxP Pex13 knockout mouse with import immunofluorescence and biochemical assays of fatty acid oxidation and plasmalogen synthesis

    PMID:12897163

    Open questions at the time
    • Did not dissect which molecular interactions drive each import pathway
    • Mechanism of peroxisome loss versus import failure not separated
  4. 2005 High

    Resolved that PEX13 uses two distinct PEX14-binding sites and PEX5 contributions to differentially support PTS1 and PTS2 import within the docking complex.

    Evidence Interaction-site mutagenesis, docking-complex co-purification, oleic acid growth, and matrix import microscopy in yeast

    PMID:15798189

    Open questions at the time
    • Performed in yeast; human site usage later shown to differ
    • Did not provide structural detail of binding surfaces
  5. 2010 High

    Connected PEX13 deficiency to mitochondria-mediated oxidative stress and neuronal death, extending its role beyond peroxisomal import to brain development.

    Evidence Brain-specific conditional knockout mouse with ROS, MnSOD, apoptosis, and mitochondrial function assays in primary cerebellar neurons

    PMID:20959636

    Open questions at the time
    • Did not establish molecular link between peroxisomal import loss and mitochondrial dysfunction
    • Did not identify the ROS source pathway
  6. 2013 High

    Identified PEX13 homooligomerization via W313 as a specific requirement for PTS1 import, separating self-association from PEX14 binding.

    Evidence Live-cell FRET, reciprocal co-immunoprecipitation, truncation constructs, and complementation in patient fibroblasts

    PMID:23716570

    Open questions at the time
    • Did not show how oligomerization mechanistically gates PTS1 cargo
    • Stoichiometry of the oligomer not defined
  7. 2016 Medium

    Revealed a non-import role for PEX13 in selective autophagy, with disease mutants specifically defective in mitophagy.

    Evidence Loss-of-function in cultured cells with Sindbis virophagy and mitophagy assays, disease-mutant complementation, and peroxin comparisons

    PMID:27827795

    Open questions at the time
    • Single lab
    • Molecular mechanism coupling PEX13 to autophagosome targeting not defined
  8. 2018 High

    Overturned the cytoplasmic-SH3 model by establishing a Nout–Cin topology placing the SH3 domain in the matrix.

    Evidence Protease-protection assays on reconstituted proteoliposomes and native rat liver peroxisomes with MS, Edman degradation, and domain-specific western blotting

    PMID:30414318

    Open questions at the time
    • Single lab
    • Did not re-map how cargo receptor PEX5 accesses the intraperoxisomal SH3 domain
  9. 2020 High

    Defined PEX13 as a suppressor of pexophagy that limits ubiquitinated PEX5 accumulation and peroxisomal ROS, and showed its downregulation during starvation.

    Evidence CRISPR knockout in cells and zebrafish with quantitative imaging, ubiquitinated-PEX5 western blotting, ROS measurement, and autophagy flux assays

    PMID:36541703

    Open questions at the time
    • Did not identify the downstream signaling cascade executing pexophagy
    • How starvation triggers PEX13 downregulation unresolved
  10. 2020 Medium

    Linked hepatic PEX13 loss to systemic iron homeostasis through SMAD7-driven hepcidin suppression and ER stress.

    Evidence Hepatocyte-specific conditional knockout mouse and HepG2/C3A siRNA with hepcidin, SMAD7, and ER stress markers

    PMID:32565019

    Open questions at the time
    • Single lab
    • Did not connect peroxisomal import defect to SMAD7 activation mechanistically
  11. 2024 High

    Provided the structural basis for PEX13 cargo recognition, showing intramolecular FxxxF–SH3 engagement that gates PEX5 WxxxF/Y binding and revealing human-specific divergence from yeast PxxP usage.

    Evidence Crystal structures with biochemical binding assays and FxxxF/WxxxF motif mutagenesis

    PMID:38632234

    Open questions at the time
    • Did not show structure within an assembled docking complex
    • Dynamics of the intramolecular switch during import not captured
  12. 2025 Medium

    Placed PEX13 downstream of the transcription factor ZBTB17/MIZ1, linking its expression to peroxisomal import capacity and purine metabolism.

    Evidence CRISPR ubiquitin-ligase screen, siRNA knockdown, transcription-factor reporter assays, metabolomics, and import microscopy

    PMID:40243840

    Open questions at the time
    • Single lab
    • Direct promoter occupancy by ZBTB17 not fully resolved
  13. 2025 Medium

    Showed viral exploitation of PEX13: a coronavirus protein degrades PEX13 to trigger pexophagy and dampen antiviral interferon signaling.

    Evidence MS identification of PEDV NSP8–PEX13 interaction, lysosomal-inhibition degradation assays, PEX5 ubiquitination, pexophagy flux, and IFN-III assays

    PMID:41186416

    Open questions at the time
    • Single lab, single virus
    • Did not map the NSP8 binding interface on PEX13
  14. 2026 Medium

    Defined the signaling cascade executing pexophagy after PEX13 loss, identifying an ATM–PINK1–STUB1–ABCD3–SQSTM1 axis.

    Evidence siRNA screening, epistasis analysis, phosphorylation and ubiquitination assays, and autophagy flux in cultured cells

    PMID:41927977

    Open questions at the time
    • Single lab
    • How PEX13 depletion is sensed by ATM upstream not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PEX13's intraperoxisomal SH3 domain physically receives cytosolic PEX5 cargo given the Nout–Cin topology, and how the import and pexophagy-suppressing functions are mechanistically coordinated, remain unresolved.
  • Topology-versus-cargo-access paradox unresolved
  • No integrated structure of the human docking/translocation complex
  • Switch between import support and pexophagy suppression undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005777 peroxisome 4
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 3 R-HSA-1430728 Metabolism 2
Partners
PEX14PEX3PEX5
Complex memberships
peroxisomal docking/translocation complex

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; expression of human PEX13 restores peroxisomal matrix protein import in PEX13-deficient cells, and a missense mutation in the SH3 domain (at a conserved position) reduces PEX13 activity. Complementation rescue in patient fibroblasts and CHO mutant cells; mutagenesis of SH3 domain; cell fusion complementation grouping American journal of human genetics High 10332040 10441330 10441568
1999 The I326T missense mutation in the SH3 domain of PEX13 is a temperature-sensitive mutation: PEX13-I326T protein is stable at 30°C but unstable at 37°C, resulting in defective peroxisomal matrix protein import at physiological temperature. Expression of mutant PEX13 cDNA in PEX13-defective CHO cells at permissive vs. restrictive temperatures; RT-PCR mutation analysis Human molecular genetics Medium 10332040
2003 Ubiquitous Pex13 knockout in mouse results in absence of morphologically intact peroxisomes, deficient import of both PTS1 and PTS2 matrix proteins, severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis, and neonatal lethality recapitulating Zellweger syndrome. Conditional Cre/loxP knockout mouse; immunofluorescence for matrix protein import; biochemical assays for fatty acid oxidation and plasmalogen in tissue and cultured fibroblasts Molecular and cellular biology High 12897163
2005 Yeast Pex13 binds Pex14 via two distinct sites: its SH3 domain and a novel intraperoxisomal site. Pex5 also contributes to the Pex13–Pex14 association. Disruption of both the intraperoxisomal Pex14-binding site of Pex13 and the Pex5–Pex14 interaction severely impairs PTS1-dependent import; additionally blocking SH3-mediated Pex13–Pex14 interaction completely abolishes PTS2 import and dissociates Pex13 from the docking complex. Mutagenesis of interaction sites; co-purification of docking complex; in vivo growth on oleic acid; fluorescence microscopy of matrix protein import Molecular and cellular biology High 15798189
2010 Brain-restricted Pex13 knockout mice exhibit defects in cerebellar fissure and cortical layer formation, granule cell migration, and Purkinje cell layer development; cultured Pex13-null cerebellar neurons show elevated reactive oxygen species, increased mitochondrial superoxide dismutase-2 (MnSOD), enhanced apoptosis, and mitochondrial dysfunction, indicating that PEX13 deficiency leads to mitochondria-mediated oxidative stress and neuronal cell death. Conditional brain-specific Cre/loxP knockout mouse; ROS measurement; immunostaining for MnSOD; apoptosis assays; mitochondrial function assays in primary cerebellar neurons Disease models & mechanisms High 20959636
2013 Human PEX13 forms homooligomers at the peroxisomal membrane; the W313 residue in the SH3 domain is required for self-association but not for interaction with PEX14. Disruption of PEX13 homooligomerization specifically impairs PTS1 protein import, and rescue of homooligomerization restores PTS1 import. The N-terminal half of PEX13 is necessary for peroxisomal localization, which is in turn required for homooligomerization. Live-cell FRET microscopy; co-immunoprecipitation; truncation constructs; complementation assays in patient fibroblasts 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. PEX13's mitophagy function is shared with PEX3 but not with PEX14 or PEX19, which are required for general autophagy. Loss-of-function (KO/KD) in cultured cells; selective autophagy assays (Sindbis virus clearance, mitochondrial clearance); complementation with disease-mutant constructs; comparison with other peroxin knockdowns EMBO reports Medium 27827795
2018 PEX13 adopts a Nout–Cin membrane topology in the peroxisomal membrane, exposing its C-terminal SH3 domain to the organelle matrix (intraperoxisomal), not to the cytoplasm as previously believed. Protease-protection assay on proteoliposomes containing PEX13 and on purified rat liver peroxisomes; mass spectrometry, Edman degradation, and domain-specific western blotting of protected fragments The FEBS journal High 30414318
2020 PEX13 loss causes accumulation of ubiquitinated PEX5 on peroxisomes; PEX13 protein level is downregulated during amino acid starvation to facilitate pexophagy induction; loss of PEX13 increases peroxisome-dependent ROS, and both ubiquitinated PEX5 accumulation and elevated ROS cooperatively induce pexophagy. CRISPR gene editing (KO) in cultured cells and zebrafish; quantitative fluorescence microscopy; western blotting for ubiquitinated PEX5; ROS measurements; autophagy flux assays Autophagy High 36541703
2024 The C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif, and this intramolecular engagement regulates binding of PEX5 WxxxF/Y motifs to the SH3 domain. Crystal structures reveal recognition of FxxxF and WxxxF/Y motifs by a non-canonical surface of the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. The canonical PxxP-binding surface of the SH3 domain does not bind PEX14 PxxP motifs in humans, unlike in yeast. Biochemical binding assays; structural biology (crystal structures); mutagenesis of FxxxF and WxxxF motifs Nature communications High 38632234
2025 The transcription factor ZBTB17/MIZ1 directly regulates PEX13 expression; knockdown of ZBTB17 reduces PEX13 levels and impairs peroxisomal matrix protein import. Knockdown of ZBTB17 or PEX13 produces similar metabolic alterations including downregulated purine synthesis, placing PEX13 downstream of ZBTB17 in a transcriptional regulatory axis. CRISPR/Cas9 ubiquitin ligase library screen; siRNA knockdown; reporter assays for transcription factor activity; metabolomic profiling; fluorescence microscopy of peroxisomal enzyme localization The Journal of cell biology Medium 40243840
2025 PEDV nonstructural protein NSP8 directly interacts with PEX13 (identified by mass spectrometry) and induces dose-dependent degradation of PEX13 via the autophagy-lysosomal pathway. PEX13 downregulation triggers ubiquitination of PEX5, which is recognized by the autophagy receptor NBR1 and ubiquitin ligase PEX2, promoting autophagic peroxisome clearance and suppressing MAVS-dependent IFN-III production. Mass spectrometry identification of NSP8–PEX13 interaction; western blotting for PEX13 degradation under lysosomal inhibition; ubiquitination assays for PEX5; pexophagy flux assays; IFN-III production assays mBio Medium 41186416
2026 PINK1 is a key regulator of pexophagy induced by PEX13 depletion; PINK1 phosphorylates STUB1, enhancing its E3 ligase activity to ubiquitinate ABCD3, which recruits SQSTM1 for peroxisomal degradation. ATM activates PINK1 under peroxisomal stress, defining an ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade downstream of PEX13 loss. siRNA screening; epistasis genetic analysis; phosphorylation and ubiquitination assays; autophagy flux assays in cultured cells Cell death and differentiation Medium 41927977
2020 PEX13 loss in mouse hepatocytes leads to reduced hepatic hepcidin expression via increased SMAD7 signaling and endoplasmic reticulum stress, disrupting systemic iron homeostasis. Conditional hepatocyte-specific Pex13 knockout mouse; siRNA knockdown in HepG2/C3A cells; hepcidin and SMAD7 western blotting; ER stress markers Biochimica et biophysica acta. Molecular basis of disease Medium 32565019

Source papers

Stage 0 corpus · 29 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 93 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
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 50 36541703
2010 Peroxisome biogenesis factor PEX13 is required for appressorium-mediated plant infection by the anthracnose fungus Colletotrichum orbiculare. Molecular plant-microbe interactions : MPMI 42 20192831
2016 Peroxisomal protein PEX13 functions in selective autophagy. EMBO reports 41 27827795
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
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
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 30 30905264
2010 Reducing PEX13 expression ameliorates physiological defects of late-acting peroxin mutants. Traffic (Copenhagen, Denmark) 30 20969679
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 26 23716570
2012 Trypanosomes contain two highly different isoforms of peroxin PEX13 involved in glycosome biogenesis. FEBS letters 23 22641036
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
2024 Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif. Nature communications 11 38632234
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
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
2025 ZBTB17/MIZ1 promotes peroxisome biogenesis by transcriptional regulation of PEX13. The Journal of cell biology 1 40243840
2025 PEDV NSP8 inhibits IFN-III production induced by MAVS through downregulation of PEX13. mBio 1 41186416
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

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