{"gene":"PEX26","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2003,"finding":"PEX26 encodes an integral peroxisomal membrane protein whose deficiency impairs peroxisomal matrix protein import; expression of PEX26 rescues peroxisome biogenesis in CG8-deficient cells, establishing PEX26 as the gene responsible for complementation group 8 peroxisome biogenesis disorders.","method":"Expression rescue in pex26 CHO cells and patient fibroblasts; immunostaining of PTS1-targeted matrix proteins; temperature-sensitivity assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — rescue experiments in multiple cell lines, replicated across patient genotypes, multiple orthogonal methods","pmids":["12851857"],"is_preprint":false},{"year":2005,"finding":"PEX26 functions as the peroxisomal docking factor for the PEX1/PEX6 AAA-ATPase heterodimer; the PEX6-binding domain was localized to the N-terminal half of PEX26 (aa 29–174). A mitochondria-targeted chimeric PEX26 (PEX26-Mito) recruits PEX6 and a fraction of PEX1 to mitochondria yet fully rescues peroxisome biogenesis, indicating peroxisomal localization of PEX26/PEX6 is not required for their function.","method":"Co-immunoprecipitation of PEX1/PEX6 with PEX26 deletion constructs; PEX26-Mito chimeric protein targeting; rescue assays in PEX26-deficient cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-mapping by Co-IP, chimeric protein rescue, multiple orthogonal methods in one study","pmids":["15858711"],"is_preprint":false},{"year":2006,"finding":"The peroxisomal targeting of the tail-anchored protein PEX26 is mediated by two C-terminal PEX19-binding sites: one overlapping the transmembrane domain and an essential luminal PEX19-binding site that prevents mislocalization to mitochondria. PEX19 is required for PEX26 import into the peroxisomal membrane. The yeast orthologue Pex15p similarly harbors a luminal PEX19-binding site acting as a peroxisomal targeting motif.","method":"Peptide array binding assays mapping PEX19-binding sites; targeting assays with truncation/chimeric constructs in cells; knockdown of PEX19; heterologous TMD insertion assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (peptide arrays, chimeric constructs, PEX19 depletion), replicated in yeast orthologue","pmids":["16763195"],"is_preprint":false},{"year":2013,"finding":"PEX19 forms a cytosolic complex with PEX26 and translocates it directly to peroxisomes by interacting with the peroxisomal membrane protein PEX3. TRC40 (the ER-targeting ATPase for tail-anchored proteins) is dispensable for peroxisomal targeting of PEX26 in mammals. Basic amino acids within the luminal domain of PEX26 are essential for PEX19 binding and thus for peroxisomal targeting.","method":"Co-immunoprecipitation of PEX19–PEX26 cytosolic complex; PEX3 interaction assay; TRC40 knockdown/dominant-negative; mutagenesis of luminal basic residues; targeting assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, knockdown of TRC40, multiple orthogonal methods in one study","pmids":["23460677"],"is_preprint":false},{"year":2018,"finding":"PEX26 undergoes homooligomerization mediated by two heptad repeat domains adjacent to its transmembrane domain. PEX26 and its splice isoform PEX26Δex5 display isoform-specific oligomerization patterns and distinct interactions with PEX2–PEX10 or PEX13–PEX14 subcomplexes, linking them to distinct pre-peroxisomal intermediates. PEX26Δex5 associates with peroxisomal membranes via a PEX14-dependent mechanism. Isoform-specific domain organization impacts peroxisomal β-oxidation and peroxisome proliferation.","method":"Co-immunoprecipitation of PEX26 isoforms with peroxin subcomplexes; heptad-repeat domain mutagenesis; peroxisomal β-oxidation assay; peroxisome proliferation assay","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutagenesis, functional assays, single lab","pmids":["30366024"],"is_preprint":false},{"year":2019,"finding":"The PEX26 F51L missense variant severely impairs binding of PEX26 to the AAA-ATPase peroxins PEX1 and PEX6, reduces PEX26 protein stability (~30% of control), and causes a temperature-sensitive defect in peroxisomal matrix protein import (PTS1, PTS2 proteins, and catalase).","method":"Co-immunoprecipitation of Pex26-F51L with PEX1/PEX6; immunofluorescence of PTS1/PTS2 proteins and catalase at 37°C vs 42°C; western blot for PEX26 protein levels; peroxisomal lipid metabolism assays in patient fibroblasts","journal":"Cold Spring Harbor molecular case studies","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with patient-derived variant, multiple orthogonal assays, single lab","pmids":["30446579"],"is_preprint":false},{"year":2021,"finding":"An organelle protein interaction screen identified 14 novel PEX26 protein-protein interactions, placing PEX26 as a hub in the peroxisomal interactome. Variant-specific disruption of these interactions (edgetic perturbations) correlates with the severity of matrix protein import defects, and the PEX26 interaction network intersects with cellular lipid metabolism. PEX26 function encompasses matrix protein import, peroxisome division and proliferation, and membrane assembly.","method":"Combined organelle protein interaction screen (Co-IP/pull-down based interactome mapping); network medicine analysis; correlation of edgetic perturbations with import phenotypes","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction screen with functional correlation, multiple PEX26 variants tested, single lab","pmids":["34804114"],"is_preprint":false},{"year":2021,"finding":"Genetic silencing of PEX26 (component of the peroxisome exportomer complex) enhances pexophagy and causes peroxisomal matrix protein import defects; this sensitizes drug-resistant cancer cells to HDACi-mediated apoptosis in an ATM kinase-dependent manner.","method":"CRISPRi silencing of PEX26; autophagosome enrichment with mass spectrometry; immunofluorescence of peroxisomal matrix proteins; ATM inhibitor rescue experiment; xenograft in vivo model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPRi with defined cellular and in vivo phenotypes, ATM inhibitor rescue, single lab","pmids":["34074205"],"is_preprint":false},{"year":2026,"finding":"The outer mitochondrial membrane E3 ubiquitin ligase MARCH5 interacts with PEX26 and facilitates transfer of newly synthesized PEX26 from the OMM to peroxisomes. In peroxisome-deficient cells, MARCH5 ubiquitinates PEX26 and targets it for p97-dependent proteasomal degradation. Knockout of PEX26 causes accumulation of Tom20-positive, catalase-deficient pre-peroxisomes, which are absent in Pex26/MARCH5 double knockout cells, supporting MARCH5 as a peroxisome biogenesis factor acting through PEX26.","method":"Co-immunoprecipitation of MARCH5 with PEX26; ubiquitination assays; p97 inhibitor experiments; Pex26 KO and Pex26/MARCH5 double KO cell lines; immunofluorescence of Tom20 and catalase","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, double KO epistasis, single preprint not yet peer-reviewed","pmids":["42182360"],"is_preprint":true}],"current_model":"PEX26 is a tail-anchored peroxisomal membrane protein that serves as the peroxisomal docking factor for the PEX1/PEX6 AAA-ATPase heterodimer (binding via its N-terminal domain, aa 29–174), thereby controlling ubiquitination and recycling of the PTS receptor PEX5 for matrix protein import; its C-terminal transmembrane and luminal domains contain two PEX19-binding sites required for PEX19-dependent, TRC40-independent targeting to peroxisomes (mediated by PEX3); it homooligomerizes via heptad-repeat domains and, in isoform-specific ways, associates with PEX14 and the PEX2–PEX10 or PEX13–PEX14 subcomplexes; newly synthesized PEX26 is transferred from the outer mitochondrial membrane to peroxisomes by the E3 ubiquitin ligase MARCH5, which also ubiquitinates PEX26 for proteasomal degradation when peroxisome biogenesis is defective."},"narrative":{"mechanistic_narrative":"PEX26 is a tail-anchored peroxisomal membrane protein essential for peroxisomal matrix protein import, and loss of its function causes complementation group 8 peroxisome biogenesis disorders [PMID:12851857]. Its central mechanistic role is to serve as the membrane docking factor for the PEX1/PEX6 AAA-ATPase heterodimer, recruiting these peroxins via an N-terminal binding domain (aa 29–174); notably, tethering this activity to mitochondria still rescues biogenesis, showing that the receptor-recycling machinery does not need to be peroxisomally localized to function [PMID:15858711]. Targeting of PEX26 to the peroxisomal membrane is PEX19-dependent and TRC40-independent: PEX19 forms a cytosolic complex with PEX26 through two C-terminal PEX19-binding sites—one overlapping the transmembrane domain and an essential luminal site containing basic residues—and delivers it directly to peroxisomes via the membrane protein PEX3 [PMID:16763195, PMID:23460677]. PEX26 homooligomerizes through heptad-repeat domains adjacent to its transmembrane segment, and isoform-specific organization couples it to distinct peroxin subcomplexes (PEX2–PEX10 or PEX13–PEX14) and thereby to β-oxidation and peroxisome proliferation [PMID:30366024]. PEX26 acts as a hub in the peroxisomal interactome, with variant-specific (edgetic) disruption of its interactions correlating with import-defect severity [PMID:34804114]. Newly synthesized PEX26 is handed off from the outer mitochondrial membrane to peroxisomes by the E3 ubiquitin ligase MARCH5, which also ubiquitinates PEX26 for p97/proteasome-dependent degradation when biogenesis is defective [PMID:42182360]. Disease-relevant missense variants such as F51L weaken PEX1/PEX6 binding, destabilize PEX26, and produce temperature-sensitive matrix import defects [PMID:30446579].","teleology":[{"year":2003,"claim":"Established that PEX26 is a bona fide peroxisome biogenesis gene by showing its deficiency blocks matrix protein import and its expression rescues the defect, answering which gene underlies complementation group 8 disorders.","evidence":"Expression rescue in pex26 CHO cells and patient fibroblasts with PTS1 matrix protein immunostaining and temperature-sensitivity assay","pmids":["12851857"],"confidence":"High","gaps":["Did not define the molecular activity of PEX26","No binding partners identified","Membrane topology and targeting route unresolved"]},{"year":2005,"claim":"Defined PEX26's molecular role as the docking factor for the PEX1/PEX6 AAA-ATPase, mapping the interaction to its N-terminal half and showing the recycling machinery functions even when displaced to mitochondria.","evidence":"Co-IP of PEX1/PEX6 with PEX26 deletion constructs and a mitochondria-targeted PEX26-Mito chimera with rescue assays","pmids":["15858711"],"confidence":"High","gaps":["Mechanism of PEX5 recycling downstream of PEX1/PEX6 docking not detailed here","How PEX26 itself reaches peroxisomes unaddressed","Stoichiometry of the docking complex unknown"]},{"year":2006,"claim":"Resolved how the tail-anchored PEX26 is targeted to peroxisomes, identifying two C-terminal PEX19-binding sites including an essential luminal motif that prevents mitochondrial mislocalization.","evidence":"Peptide array PEX19-binding mapping, truncation/chimeric targeting constructs, PEX19 knockdown, conserved in yeast Pex15p","pmids":["16763195"],"confidence":"High","gaps":["Did not establish the membrane insertion machinery beyond PEX19 dependence","Role of PEX3 not yet defined","TRC40 involvement not tested"]},{"year":2013,"claim":"Showed PEX19 carries PEX26 as a cytosolic complex and delivers it via PEX3 in a TRC40-independent manner, distinguishing peroxisomal from canonical tail-anchored ER targeting.","evidence":"Reciprocal Co-IP of PEX19–PEX26, PEX3 interaction assay, TRC40 knockdown/dominant-negative, luminal basic-residue mutagenesis","pmids":["23460677"],"confidence":"High","gaps":["Structural basis of PEX19–PEX26 recognition not resolved","Energetics of membrane insertion via PEX3 unclear","Whether mitochondria are an obligatory intermediate not addressed here"]},{"year":2018,"claim":"Demonstrated that PEX26 homooligomerizes via heptad-repeat domains and that splice isoforms engage distinct peroxin subcomplexes, linking PEX26 to specific pre-peroxisomal intermediates and to β-oxidation and proliferation.","evidence":"Co-IP of PEX26 isoforms with peroxin subcomplexes, heptad-repeat mutagenesis, β-oxidation and proliferation assays","pmids":["30366024"],"confidence":"Medium","gaps":["Single lab; isoform-specific roles not independently confirmed","Functional significance of PEX26Δex5 in vivo unclear","Oligomer architecture not structurally defined"]},{"year":2019,"claim":"Linked a specific patient missense variant (F51L) to impaired PEX1/PEX6 binding, reduced PEX26 stability, and temperature-sensitive import failure, connecting genotype to molecular mechanism.","evidence":"Co-IP of Pex26-F51L with PEX1/PEX6, immunofluorescence of PTS1/PTS2/catalase at 37 vs 42°C, western blot, lipid metabolism assays in patient fibroblasts","pmids":["30446579"],"confidence":"Medium","gaps":["Single variant in one patient background","Structural basis of binding loss not determined","Degradation pathway for destabilized variant not identified"]},{"year":2021,"claim":"Positioned PEX26 as a peroxisomal interactome hub and showed that variant-specific (edgetic) disruption of its interactions tracks with import-defect severity.","evidence":"Organelle protein interaction screen, network medicine analysis, correlation of edgetic perturbations with import phenotypes","pmids":["34804114"],"confidence":"Medium","gaps":["Many novel interactions not individually validated","Direct vs indirect partners not distinguished","Single lab screen"]},{"year":2021,"claim":"Revealed a functional consequence of PEX26 loss beyond biogenesis: silencing enhances pexophagy and sensitizes drug-resistant cancer cells to HDACi apoptosis via ATM.","evidence":"CRISPRi silencing, autophagosome MS enrichment, matrix protein immunofluorescence, ATM inhibitor rescue, xenograft model","pmids":["34074205"],"confidence":"Medium","gaps":["Mechanism linking import defect to ATM signaling not detailed","Generality across cancer types untested","Single lab"]},{"year":2026,"claim":"Identified MARCH5 as a mitochondrial E3 ligase that transfers newly synthesized PEX26 from the OMM to peroxisomes and degrades it via p97 when biogenesis fails, defining a quality-control and delivery route for PEX26.","evidence":"Reciprocal Co-IP of MARCH5–PEX26, ubiquitination assays, p97 inhibitor experiments, Pex26 and Pex26/MARCH5 double KO with Tom20/catalase immunofluorescence (preprint)","pmids":["42182360"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Whether OMM transit is obligatory for all PEX26 unresolved","Relationship between MARCH5-mediated delivery and PEX19/PEX3 targeting unclear"]},{"year":null,"claim":"How PEX26-mediated PEX1/PEX6 docking is mechanistically and structurally coupled to PEX5 ubiquitination and dislocation during the matrix import cycle remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the PEX26–PEX1–PEX6 assembly","Order of MARCH5 vs PEX19/PEX3 targeting steps undefined","Physiological role of isoform-specific subcomplex partitioning unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3]}],"complexes":["peroxisome exportomer (PEX1/PEX6 docking complex)"],"partners":["PEX1","PEX6","PEX19","PEX3","PEX14","MARCH5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z412","full_name":"Peroxisome assembly protein 26","aliases":["Peroxin-26"],"length_aa":305,"mass_kda":33.9,"function":"Peroxisomal docking factor that anchors PEX1 and PEX6 to peroxisome membranes (PubMed:12717447, PubMed:12851857, PubMed:16257970, PubMed:16763195, PubMed:16854980, PubMed:21362118). PEX26 is therefore required for the formation of the PEX1-PEX6 AAA ATPase complex, a complex that mediates the extraction of the PEX5 receptor from peroxisomal membrane (PubMed:12717447, PubMed:12851857, PubMed:16257970, PubMed:16763195, PubMed:16854980, PubMed:21362118)","subcellular_location":"Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/Q7Z412/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEX26","classification":"Not Classified","n_dependent_lines":56,"n_total_lines":1208,"dependency_fraction":0.046357615894039736},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEX26","total_profiled":1310},"omim":[{"mim_id":"614873","title":"PEROXISOME BIOGENESIS DISORDER 7B; PBD7B","url":"https://www.omim.org/entry/614873"},{"mim_id":"614872","title":"PEROXISOME BIOGENESIS DISORDER 7A (ZELLWEGER); PBD7A","url":"https://www.omim.org/entry/614872"},{"mim_id":"608666","title":"PEROXISOME BIOGENESIS FACTOR 26; PEX26","url":"https://www.omim.org/entry/608666"},{"mim_id":"601539","title":"PEROXISOME BIOGENESIS DISORDER 1B; PBD1B","url":"https://www.omim.org/entry/601539"},{"mim_id":"214100","title":"PEROXISOME BIOGENESIS DISORDER 1A (ZELLWEGER); PBD1A","url":"https://www.omim.org/entry/214100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PEX26"},"hgnc":{"alias_symbol":["FLJ20695"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z412","domains":[{"cath_id":"1.25.40","chopping":"32-171","consensus_level":"medium","plddt":93.4572,"start":32,"end":171}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z412","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z412-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z412-F1-predicted_aligned_error_v6.png","plddt_mean":79.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEX26","jax_strain_url":"https://www.jax.org/strain/search?query=PEX26"},"sequence":{"accession":"Q7Z412","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z412.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z412/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z412"}},"corpus_meta":[{"pmid":"16763195","id":"PMC_16763195","title":"Targeting of the tail-anchored peroxisomal membrane proteins PEX26 and PEX15 occurs through C-terminal PEX19-binding sites.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16763195","citation_count":105,"is_preprint":false},{"pmid":"23460677","id":"PMC_23460677","title":"Tail-anchored PEX26 targets peroxisomes via a PEX19-dependent and TRC40-independent class I pathway.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23460677","citation_count":81,"is_preprint":false},{"pmid":"12851857","id":"PMC_12851857","title":"Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12851857","citation_count":68,"is_preprint":false},{"pmid":"28944237","id":"PMC_28944237","title":"Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome.","date":"2017","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28944237","citation_count":53,"is_preprint":false},{"pmid":"15858711","id":"PMC_15858711","title":"Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15858711","citation_count":43,"is_preprint":false},{"pmid":"34074205","id":"PMC_34074205","title":"Silencing PEX26 as an unconventional mode to kill drug-resistant cancer cells and forestall drug resistance.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34074205","citation_count":17,"is_preprint":false},{"pmid":"30446579","id":"PMC_30446579","title":"A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder.","date":"2019","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/30446579","citation_count":15,"is_preprint":false},{"pmid":"30366024","id":"PMC_30366024","title":"Isoform-specific domain organization determines conformation and function of the peroxisomal biogenesis factor PEX26.","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30366024","citation_count":12,"is_preprint":false},{"pmid":"33926089","id":"PMC_33926089","title":"Identification of a Homozygous PEX26 Mutation in a Heimler Syndrome Patient.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33926089","citation_count":8,"is_preprint":false},{"pmid":"34430430","id":"PMC_34430430","title":"PEX26 gene genotype-phenotype correlation in neonates with Zellweger syndrome.","date":"2021","source":"Translational pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34430430","citation_count":5,"is_preprint":false},{"pmid":"37957408","id":"PMC_37957408","title":"PEX26 Functions as a Metastasis Suppressor in Colorectal Cancer.","date":"2023","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37957408","citation_count":3,"is_preprint":false},{"pmid":"33912394","id":"PMC_33912394","title":"A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder.","date":"2021","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/33912394","citation_count":3,"is_preprint":false},{"pmid":"39757991","id":"PMC_39757991","title":"Zellweger syndrome; identification of mutations in PEX19 and PEX26 gene in Saudi families.","date":"2025","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39757991","citation_count":2,"is_preprint":false},{"pmid":"34804114","id":"PMC_34804114","title":"Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34804114","citation_count":2,"is_preprint":false},{"pmid":"39359950","id":"PMC_39359950","title":"Biallelic Deletion of PEX26 Exon 4 in a Boy with Phenotypic Features of both Zellweger Syndrome and Infantile Refsum Disease.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/39359950","citation_count":1,"is_preprint":false},{"pmid":"38323187","id":"PMC_38323187","title":"Identification of a novel heterozygous variant in the PEX26 gene in an infant: a case report.","date":"2024","source":"Translational pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38323187","citation_count":1,"is_preprint":false},{"pmid":"42182360","id":"PMC_42182360","title":"Dual role of the OMM E3 Ub ligase MARCH5 in de novo peroxisome biogenesis and mitochondrial quality control through direct regulation of Pex26.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42182360","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11558,"output_tokens":2828,"usd":0.038547,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10052,"output_tokens":3713,"usd":0.071542,"stage2_stop_reason":"end_turn"},"total_usd":0.110089,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PEX26 encodes an integral peroxisomal membrane protein whose deficiency impairs peroxisomal matrix protein import; expression of PEX26 rescues peroxisome biogenesis in CG8-deficient cells, establishing PEX26 as the gene responsible for complementation group 8 peroxisome biogenesis disorders.\",\n      \"method\": \"Expression rescue in pex26 CHO cells and patient fibroblasts; immunostaining of PTS1-targeted matrix proteins; temperature-sensitivity assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rescue experiments in multiple cell lines, replicated across patient genotypes, multiple orthogonal methods\",\n      \"pmids\": [\"12851857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PEX26 functions as the peroxisomal docking factor for the PEX1/PEX6 AAA-ATPase heterodimer; the PEX6-binding domain was localized to the N-terminal half of PEX26 (aa 29–174). A mitochondria-targeted chimeric PEX26 (PEX26-Mito) recruits PEX6 and a fraction of PEX1 to mitochondria yet fully rescues peroxisome biogenesis, indicating peroxisomal localization of PEX26/PEX6 is not required for their function.\",\n      \"method\": \"Co-immunoprecipitation of PEX1/PEX6 with PEX26 deletion constructs; PEX26-Mito chimeric protein targeting; rescue assays in PEX26-deficient cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-mapping by Co-IP, chimeric protein rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15858711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The peroxisomal targeting of the tail-anchored protein PEX26 is mediated by two C-terminal PEX19-binding sites: one overlapping the transmembrane domain and an essential luminal PEX19-binding site that prevents mislocalization to mitochondria. PEX19 is required for PEX26 import into the peroxisomal membrane. The yeast orthologue Pex15p similarly harbors a luminal PEX19-binding site acting as a peroxisomal targeting motif.\",\n      \"method\": \"Peptide array binding assays mapping PEX19-binding sites; targeting assays with truncation/chimeric constructs in cells; knockdown of PEX19; heterologous TMD insertion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (peptide arrays, chimeric constructs, PEX19 depletion), replicated in yeast orthologue\",\n      \"pmids\": [\"16763195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PEX19 forms a cytosolic complex with PEX26 and translocates it directly to peroxisomes by interacting with the peroxisomal membrane protein PEX3. TRC40 (the ER-targeting ATPase for tail-anchored proteins) is dispensable for peroxisomal targeting of PEX26 in mammals. Basic amino acids within the luminal domain of PEX26 are essential for PEX19 binding and thus for peroxisomal targeting.\",\n      \"method\": \"Co-immunoprecipitation of PEX19–PEX26 cytosolic complex; PEX3 interaction assay; TRC40 knockdown/dominant-negative; mutagenesis of luminal basic residues; targeting assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, knockdown of TRC40, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23460677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PEX26 undergoes homooligomerization mediated by two heptad repeat domains adjacent to its transmembrane domain. PEX26 and its splice isoform PEX26Δex5 display isoform-specific oligomerization patterns and distinct interactions with PEX2–PEX10 or PEX13–PEX14 subcomplexes, linking them to distinct pre-peroxisomal intermediates. PEX26Δex5 associates with peroxisomal membranes via a PEX14-dependent mechanism. Isoform-specific domain organization impacts peroxisomal β-oxidation and peroxisome proliferation.\",\n      \"method\": \"Co-immunoprecipitation of PEX26 isoforms with peroxin subcomplexes; heptad-repeat domain mutagenesis; peroxisomal β-oxidation assay; peroxisome proliferation assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutagenesis, functional assays, single lab\",\n      \"pmids\": [\"30366024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The PEX26 F51L missense variant severely impairs binding of PEX26 to the AAA-ATPase peroxins PEX1 and PEX6, reduces PEX26 protein stability (~30% of control), and causes a temperature-sensitive defect in peroxisomal matrix protein import (PTS1, PTS2 proteins, and catalase).\",\n      \"method\": \"Co-immunoprecipitation of Pex26-F51L with PEX1/PEX6; immunofluorescence of PTS1/PTS2 proteins and catalase at 37°C vs 42°C; western blot for PEX26 protein levels; peroxisomal lipid metabolism assays in patient fibroblasts\",\n      \"journal\": \"Cold Spring Harbor molecular case studies\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with patient-derived variant, multiple orthogonal assays, single lab\",\n      \"pmids\": [\"30446579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An organelle protein interaction screen identified 14 novel PEX26 protein-protein interactions, placing PEX26 as a hub in the peroxisomal interactome. Variant-specific disruption of these interactions (edgetic perturbations) correlates with the severity of matrix protein import defects, and the PEX26 interaction network intersects with cellular lipid metabolism. PEX26 function encompasses matrix protein import, peroxisome division and proliferation, and membrane assembly.\",\n      \"method\": \"Combined organelle protein interaction screen (Co-IP/pull-down based interactome mapping); network medicine analysis; correlation of edgetic perturbations with import phenotypes\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction screen with functional correlation, multiple PEX26 variants tested, single lab\",\n      \"pmids\": [\"34804114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic silencing of PEX26 (component of the peroxisome exportomer complex) enhances pexophagy and causes peroxisomal matrix protein import defects; this sensitizes drug-resistant cancer cells to HDACi-mediated apoptosis in an ATM kinase-dependent manner.\",\n      \"method\": \"CRISPRi silencing of PEX26; autophagosome enrichment with mass spectrometry; immunofluorescence of peroxisomal matrix proteins; ATM inhibitor rescue experiment; xenograft in vivo model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPRi with defined cellular and in vivo phenotypes, ATM inhibitor rescue, single lab\",\n      \"pmids\": [\"34074205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The outer mitochondrial membrane E3 ubiquitin ligase MARCH5 interacts with PEX26 and facilitates transfer of newly synthesized PEX26 from the OMM to peroxisomes. In peroxisome-deficient cells, MARCH5 ubiquitinates PEX26 and targets it for p97-dependent proteasomal degradation. Knockout of PEX26 causes accumulation of Tom20-positive, catalase-deficient pre-peroxisomes, which are absent in Pex26/MARCH5 double knockout cells, supporting MARCH5 as a peroxisome biogenesis factor acting through PEX26.\",\n      \"method\": \"Co-immunoprecipitation of MARCH5 with PEX26; ubiquitination assays; p97 inhibitor experiments; Pex26 KO and Pex26/MARCH5 double KO cell lines; immunofluorescence of Tom20 and catalase\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, double KO epistasis, single preprint not yet peer-reviewed\",\n      \"pmids\": [\"42182360\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PEX26 is a tail-anchored peroxisomal membrane protein that serves as the peroxisomal docking factor for the PEX1/PEX6 AAA-ATPase heterodimer (binding via its N-terminal domain, aa 29–174), thereby controlling ubiquitination and recycling of the PTS receptor PEX5 for matrix protein import; its C-terminal transmembrane and luminal domains contain two PEX19-binding sites required for PEX19-dependent, TRC40-independent targeting to peroxisomes (mediated by PEX3); it homooligomerizes via heptad-repeat domains and, in isoform-specific ways, associates with PEX14 and the PEX2–PEX10 or PEX13–PEX14 subcomplexes; newly synthesized PEX26 is transferred from the outer mitochondrial membrane to peroxisomes by the E3 ubiquitin ligase MARCH5, which also ubiquitinates PEX26 for proteasomal degradation when peroxisome biogenesis is defective.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PEX26 is a tail-anchored peroxisomal membrane protein essential for peroxisomal matrix protein import, and loss of its function causes complementation group 8 peroxisome biogenesis disorders [#0]. Its central mechanistic role is to serve as the membrane docking factor for the PEX1/PEX6 AAA-ATPase heterodimer, recruiting these peroxins via an N-terminal binding domain (aa 29\\u2013174); notably, tethering this activity to mitochondria still rescues biogenesis, showing that the receptor-recycling machinery does not need to be peroxisomally localized to function [#1]. Targeting of PEX26 to the peroxisomal membrane is PEX19-dependent and TRC40-independent: PEX19 forms a cytosolic complex with PEX26 through two C-terminal PEX19-binding sites\\u2014one overlapping the transmembrane domain and an essential luminal site containing basic residues\\u2014and delivers it directly to peroxisomes via the membrane protein PEX3 [#2, #3]. PEX26 homooligomerizes through heptad-repeat domains adjacent to its transmembrane segment, and isoform-specific organization couples it to distinct peroxin subcomplexes (PEX2\\u2013PEX10 or PEX13\\u2013PEX14) and thereby to \\u03b2-oxidation and peroxisome proliferation [#4]. PEX26 acts as a hub in the peroxisomal interactome, with variant-specific (edgetic) disruption of its interactions correlating with import-defect severity [#6]. Newly synthesized PEX26 is handed off from the outer mitochondrial membrane to peroxisomes by the E3 ubiquitin ligase MARCH5, which also ubiquitinates PEX26 for p97/proteasome-dependent degradation when biogenesis is defective [#8]. Disease-relevant missense variants such as F51L weaken PEX1/PEX6 binding, destabilize PEX26, and produce temperature-sensitive matrix import defects [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that PEX26 is a bona fide peroxisome biogenesis gene by showing its deficiency blocks matrix protein import and its expression rescues the defect, answering which gene underlies complementation group 8 disorders.\",\n      \"evidence\": \"Expression rescue in pex26 CHO cells and patient fibroblasts with PTS1 matrix protein immunostaining and temperature-sensitivity assay\",\n      \"pmids\": [\"12851857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity of PEX26\", \"No binding partners identified\", \"Membrane topology and targeting route unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined PEX26's molecular role as the docking factor for the PEX1/PEX6 AAA-ATPase, mapping the interaction to its N-terminal half and showing the recycling machinery functions even when displaced to mitochondria.\",\n      \"evidence\": \"Co-IP of PEX1/PEX6 with PEX26 deletion constructs and a mitochondria-targeted PEX26-Mito chimera with rescue assays\",\n      \"pmids\": [\"15858711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PEX5 recycling downstream of PEX1/PEX6 docking not detailed here\", \"How PEX26 itself reaches peroxisomes unaddressed\", \"Stoichiometry of the docking complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how the tail-anchored PEX26 is targeted to peroxisomes, identifying two C-terminal PEX19-binding sites including an essential luminal motif that prevents mitochondrial mislocalization.\",\n      \"evidence\": \"Peptide array PEX19-binding mapping, truncation/chimeric targeting constructs, PEX19 knockdown, conserved in yeast Pex15p\",\n      \"pmids\": [\"16763195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the membrane insertion machinery beyond PEX19 dependence\", \"Role of PEX3 not yet defined\", \"TRC40 involvement not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed PEX19 carries PEX26 as a cytosolic complex and delivers it via PEX3 in a TRC40-independent manner, distinguishing peroxisomal from canonical tail-anchored ER targeting.\",\n      \"evidence\": \"Reciprocal Co-IP of PEX19\\u2013PEX26, PEX3 interaction assay, TRC40 knockdown/dominant-negative, luminal basic-residue mutagenesis\",\n      \"pmids\": [\"23460677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PEX19\\u2013PEX26 recognition not resolved\", \"Energetics of membrane insertion via PEX3 unclear\", \"Whether mitochondria are an obligatory intermediate not addressed here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that PEX26 homooligomerizes via heptad-repeat domains and that splice isoforms engage distinct peroxin subcomplexes, linking PEX26 to specific pre-peroxisomal intermediates and to \\u03b2-oxidation and proliferation.\",\n      \"evidence\": \"Co-IP of PEX26 isoforms with peroxin subcomplexes, heptad-repeat mutagenesis, \\u03b2-oxidation and proliferation assays\",\n      \"pmids\": [\"30366024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; isoform-specific roles not independently confirmed\", \"Functional significance of PEX26\\u0394ex5 in vivo unclear\", \"Oligomer architecture not structurally defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked a specific patient missense variant (F51L) to impaired PEX1/PEX6 binding, reduced PEX26 stability, and temperature-sensitive import failure, connecting genotype to molecular mechanism.\",\n      \"evidence\": \"Co-IP of Pex26-F51L with PEX1/PEX6, immunofluorescence of PTS1/PTS2/catalase at 37 vs 42\\u00b0C, western blot, lipid metabolism assays in patient fibroblasts\",\n      \"pmids\": [\"30446579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant in one patient background\", \"Structural basis of binding loss not determined\", \"Degradation pathway for destabilized variant not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned PEX26 as a peroxisomal interactome hub and showed that variant-specific (edgetic) disruption of its interactions tracks with import-defect severity.\",\n      \"evidence\": \"Organelle protein interaction screen, network medicine analysis, correlation of edgetic perturbations with import phenotypes\",\n      \"pmids\": [\"34804114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many novel interactions not individually validated\", \"Direct vs indirect partners not distinguished\", \"Single lab screen\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a functional consequence of PEX26 loss beyond biogenesis: silencing enhances pexophagy and sensitizes drug-resistant cancer cells to HDACi apoptosis via ATM.\",\n      \"evidence\": \"CRISPRi silencing, autophagosome MS enrichment, matrix protein immunofluorescence, ATM inhibitor rescue, xenograft model\",\n      \"pmids\": [\"34074205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking import defect to ATM signaling not detailed\", \"Generality across cancer types untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified MARCH5 as a mitochondrial E3 ligase that transfers newly synthesized PEX26 from the OMM to peroxisomes and degrades it via p97 when biogenesis fails, defining a quality-control and delivery route for PEX26.\",\n      \"evidence\": \"Reciprocal Co-IP of MARCH5\\u2013PEX26, ubiquitination assays, p97 inhibitor experiments, Pex26 and Pex26/MARCH5 double KO with Tom20/catalase immunofluorescence (preprint)\",\n      \"pmids\": [\"42182360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Whether OMM transit is obligatory for all PEX26 unresolved\", \"Relationship between MARCH5-mediated delivery and PEX19/PEX3 targeting unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PEX26-mediated PEX1/PEX6 docking is mechanistically and structurally coupled to PEX5 ubiquitination and dislocation during the matrix import cycle remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the PEX26\\u2013PEX1\\u2013PEX6 assembly\", \"Order of MARCH5 vs PEX19/PEX3 targeting steps undefined\", \"Physiological role of isoform-specific subcomplex partitioning unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005778\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"peroxisome exportomer (PEX1/PEX6 docking complex)\"],\n    \"partners\": [\"PEX1\", \"PEX6\", \"PEX19\", \"PEX3\", \"PEX14\", \"MARCH5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}