PEX26

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).

1. 2003 High

   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

   PMID:12851857

   Open questions at the time

   • Did not define the molecular activity of PEX26
   • No binding partners identified
   • Membrane topology and targeting route unresolved
2. 2005 High

   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

   PMID:15858711

   Open questions at the time

   • Mechanism of PEX5 recycling downstream of PEX1/PEX6 docking not detailed here
   • How PEX26 itself reaches peroxisomes unaddressed
   • Stoichiometry of the docking complex unknown
3. 2006 High

   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

   PMID:16763195

   Open questions at the time

   • Did not establish the membrane insertion machinery beyond PEX19 dependence
   • Role of PEX3 not yet defined
   • TRC40 involvement not tested
4. 2013 High

   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

   PMID:23460677

   Open questions at the time

   • Structural basis of PEX19–PEX26 recognition not resolved
   • Energetics of membrane insertion via PEX3 unclear
   • Whether mitochondria are an obligatory intermediate not addressed here
5. 2018 Medium

   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

   PMID:30366024

   Open questions at the time

   • Single lab; isoform-specific roles not independently confirmed
   • Functional significance of PEX26Δex5 in vivo unclear
   • Oligomer architecture not structurally defined
6. 2019 Medium

   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

   PMID:30446579

   Open questions at the time

   • Single variant in one patient background
   • Structural basis of binding loss not determined
   • Degradation pathway for destabilized variant not identified
7. 2021 Medium

   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

   PMID:34804114

   Open questions at the time

   • Many novel interactions not individually validated
   • Direct vs indirect partners not distinguished
   • Single lab screen
8. 2021 Medium

   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

   PMID:34074205

   Open questions at the time

   • Mechanism linking import defect to ATM signaling not detailed
   • Generality across cancer types untested
   • Single lab
9. 2026 Medium

   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)

   PMID:42182360

   Open questions at the time

   • Preprint not yet peer-reviewed
   • Whether OMM transit is obligatory for all PEX26 unresolved
   • Relationship between MARCH5-mediated delivery and PEX19/PEX3 targeting unclear

• How PEX26-mediated PEX1/PEX6 docking is mechanistically and structurally coupled to PEX5 ubiquitination and dislocation during the matrix import cycle remains unresolved.
• 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