{"gene":"PEX11B","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1998,"finding":"Overexpression of PEX11β alone is sufficient to induce peroxisome proliferation in the absence of extracellular stimuli, acting through a multistep process involving peroxisome elongation, segregation of PEX11β from other peroxisomal membrane proteins, followed by peroxisome division.","method":"Overexpression of human PEX11β in mammalian cells with time-course microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean overexpression with defined morphological phenotype, replicated across multiple studies confirming the elongation-then-division mechanism","pmids":["9792670"],"is_preprint":false},{"year":1998,"finding":"PEX11β is a peroxisomal membrane protein whose mRNA levels are similar across all rat tissues examined and are unaffected by peroxisome-proliferating agents, implicating it in constitutive (rather than stimulus-induced) control of peroxisome abundance.","method":"Northern blot analysis of rat tissues treated with peroxisome proliferators (clofibrate, DEHP)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA quantification in multiple tissues and conditions, single lab","pmids":["9792670"],"is_preprint":false},{"year":2012,"finding":"A homozygous nonsense mutation in PEX11β causes an isolated peroxisome division defect without affecting standard peroxisomal metabolic parameters, and the division defect is exacerbated at 40°C correlating with decreased PEX11γ expression.","method":"Patient fibroblast biochemical/microscopic analysis, Sanger sequencing of PEX11β, temperature-shift experiments","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in patient cells with defined cellular phenotype, single lab with orthogonal biochemical and microscopy methods","pmids":["22581968"],"is_preprint":false},{"year":2012,"finding":"PEX11β, but not PEX11α or PEX11γ, is almost exclusively extracted from peroxisomal membranes of paraformaldehyde-fixed cells by Triton X-100 permeabilization, indicating biochemically distinct membrane association properties of PEX11β compared to other isoforms; loss can be prevented by digitonin permeabilization, glutaraldehyde fixation, or large protein tag (YFP) fusion.","method":"Detergent extraction assay (Triton X-100 vs digitonin) on PFA-fixed cells, immunofluorescence, western blot of detergent fractions","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation with orthogonal isoform comparisons, single lab","pmids":["22875152"],"is_preprint":false},{"year":2011,"finding":"Deletion of both alleles of Pex11β in mice reduces peroxisome number by ~30%, causes increased oxidative stress, delayed neuronal development, and neuronal death; heterozygous deletion (one allele) slightly increases peroxisome abundance yet also causes oxidative stress and partial neuronal death, with partial compensation via SOD2 upregulation.","method":"Pex11β knockout and heterozygous mouse models; primary neuronal cultures; immunofluorescence; mRNA/protein quantification of neuronal markers; ROS assays","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal readouts (peroxisome number, oxidative stress markers, neuronal differentiation markers), replicated in vivo and in vitro","pmids":["21954064"],"is_preprint":false},{"year":2019,"finding":"Inactivation of PEX11B (via CRISPR-Cas9) does not affect H2O2 permeation across the peroxisomal membrane but unexpectedly leads to partial mislocalization of both peroxisomal membrane and matrix proteins to mitochondria and a decrease in peroxisome density, suggesting a role for PEX11B in peroxisomal protein sorting.","method":"CRISPR-Cas9 knockout of PEX11B in Flp-In T-REx 293 cells; controlled intracellular H2O2 generation assay; immunofluorescence and subcellular fractionation","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with orthogonal localization and functional assays, single lab","pmids":["31129117"],"is_preprint":false},{"year":2022,"finding":"PEX11β can promote peroxisome division in the absence of MFF (mitochondrial fission factor) through a DRP1- and FIS1-dependent alternative pathway; MFF can restore peroxisome morphology in PEX11β-deficient patient cells independently of PEX11β; targeting PEX11β to mitochondria induces mitochondrial division.","method":"siRNA/shRNA knockdown of MFF, FIS1, DRP1; PEX11β-deficient patient cells; mitochondria-targeted PEX11β constructs; live-cell and fixed immunofluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic perturbations (MFF KD, FIS1 KD, DRP1 KD, patient cells) with defined morphological phenotypes and orthogonal targeting experiments, single lab with comprehensive controls","pmids":["35678336"],"is_preprint":false},{"year":2020,"finding":"A functional SMAD2/3 binding site is present in the PEX11β promoter; TGFβ signaling induces peroxisome elongation (a prerequisite for proliferation) and correlates with time-resolved upregulation of PEX11β mRNA but not PEX11α or PEX11γ, placing PEX11β downstream of the TGFβ/SMAD2/3 transcriptional axis.","method":"Cell-based peroxisome proliferation assay; time-resolved mRNA expression profiling; promoter analysis with SMAD2/3 binding site identification; TGFβ treatment","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional promoter binding site identified, correlative mRNA changes with TGFβ, single lab; functional SMAD binding established but full mechanistic epistasis not completely reconstituted","pmids":["33195217"],"is_preprint":false},{"year":2022,"finding":"ISOC1 deficiency activates AKT1, and overactivation of AKT1 reduces the stability of PEX11B through protein modification (post-translational), thereby reducing peroxisome biogenesis and affecting inflammatory cytokine production in macrophages.","method":"ISOC1 siRNA knockdown in LPS-treated RAW264.7 macrophages; AKT1 overexpression/inhibition; PEX11B stability assays; cytokine measurement","journal":"Molecules (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell system; the nature of 'protein modification' is not specified in the abstract; limited mechanistic detail","pmids":["36144632"],"is_preprint":false},{"year":2022,"finding":"In fibroblasts from patients deficient in PEX11β (as well as DLP1 and NME3), docosahexaenoic acid (DHA)-containing phospholipids are decreased and arachidonic acid/oleic acid levels are elevated, establishing that PEX11β-dependent peroxisome morphology/dynamics affect phospholipid fatty acid composition.","method":"Phospholipid composition analysis (lipidomics) of patient fibroblasts (PEX11β-deficient) and Pex11β-KO mouse embryonic fibroblasts","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in patient cells and KO mouse fibroblasts with direct lipid measurement; multiple genetic backgrounds tested","pmids":["36522796"],"is_preprint":false},{"year":2025,"finding":"Palmitic acid (PA) induces palmitoylation of PEX11B at the C25 site, which disrupts PEX11B self-interaction and impedes peroxisome elongation, reducing peroxisomal biogenesis in Schwann cells.","method":"Acyl-RAC assay and acyl-biotin exchange (ABE) assay for palmitoylation detection; site-directed mutagenesis of C25; laser confocal super-resolution imaging; western blot","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical palmitoylation assays with site-specific mutagenesis and functional readout, single lab","pmids":["39934809"],"is_preprint":false},{"year":2013,"finding":"Knockdown of Pex11β in Xenopus laevis A6 kidney cells decreases mRNA levels of Pex1, PMP70, and PPARγ, reduces PMP70 protein and peroxisome-like structures, and results in increased cellular H2O2 and mitochondrial reactive oxygen species.","method":"Morpholino-mediated knockdown; qRT-PCR; immunofluorescence; Amplex Red, DCFDA, and MitoTracker ROS assays","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts in Xenopus ortholog model, single lab","pmids":["24234511"],"is_preprint":false},{"year":2026,"finding":"PEX11β knockout in human iPSC-derived neural progenitors causes elongated peroxisomal morphology and reduced peroxisomal fission with impaired recruitment of fission proteins, without affecting mitochondrial morphology or respiration; lipidomic analysis showed reduced ether-linked phospholipids in PEX11β-deficient neural progenitors; elongated peroxisomal morphology was independent of the peroxisome-endoplasmic reticulum tether.","method":"CRISPR/Cas9 knockout of PEX11β in human iPSCs differentiated to neural progenitors and neural rosettes; live imaging; lipidomics; fission protein recruitment assays; mitochondrial respiration measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous KO with multiple orthogonal methods in human iPSC-derived model; preprint, not yet peer-reviewed","pmids":["41756896"],"is_preprint":true},{"year":2025,"finding":"PKC activation promotes PEX11β-dependent peroxisome formation through inactivation of GSK3β, which promotes peroxisome-ER contact site formation; removal of VAPA and VAPB impairs PEX11β-dependent peroxisome biogenesis and PKC regulation.","method":"PKC activator/inhibitor treatment; GSK3β inhibition; VAPA/VAPB knockdown; live-cell imaging of peroxisome numbers; peroxisome-ER contact site assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, pathway placement based on pharmacological perturbations without direct biochemical interaction between PKC and PEX11β demonstrated","pmids":["bio_10.1101_2025.01.21.634043"],"is_preprint":true},{"year":2025,"finding":"PEX11B knockout in sheep OA3.Ts cells increases susceptibility to orf virus (ORFV) infection; mechanistically, PEX11B loss disrupts peroxisomal integrity and lipid metabolism, leading to increased plasma membrane fluidity that promotes viral entry and replication.","method":"Genome-wide CRISPR knockout screen in sheep OA3.Ts cells; PEX11B KO validation; viral infection assays; membrane fluidity measurements; lipid metabolism analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, novel antiviral function with mechanistic link through membrane fluidity but limited biochemical detail in abstract","pmids":["bio_10.1101_2025.11.28.691156"],"is_preprint":true}],"current_model":"PEX11β is a peroxisomal membrane protein that drives peroxisome proliferation by initiating membrane elongation, segregating from other peroxisomal membrane proteins, and then cooperating with DRP1/FIS1 (and in parallel with MFF) to execute fission; its activity is regulated at the transcriptional level by TGFβ/SMAD2/3 signaling and post-translationally by AKT1-mediated destabilization and palmitoylation at C25 (which disrupts self-interaction and blocks elongation), while its loss impairs DHA-containing phospholipid metabolism, increases oxidative stress, and causes neurodevelopmental defects."},"narrative":{"mechanistic_narrative":"PEX11β is a peroxisomal membrane protein that functions as the master driver of peroxisome proliferation, and its overexpression alone is sufficient to induce proliferation through an ordered multistep program of membrane elongation, segregation of PEX11β from other peroxisomal membrane proteins, and subsequent division [PMID:9792670]. Unlike inducible isoforms, PEX11β is expressed constitutively across tissues and is insensitive to peroxisome-proliferating agents, marking it as the basal regulator of peroxisome abundance [PMID:9792670]; it also possesses biochemically distinct membrane-association properties relative to PEX11α and PEX11γ [PMID:22875152]. PEX11β initiates the elongation step and then cooperates with the fission machinery—DRP1 and FIS1—to execute division, operating in parallel to MFF such that it can drive division even when MFF is absent [PMID:35678336]. Its proliferative activity is gated transcriptionally downstream of TGFβ/SMAD2/3 signaling via a functional SMAD2/3 site in the PEX11β promoter [PMID:33195217], and post-translationally by palmitoylation at Cys25, which disrupts PEX11β self-interaction and blocks elongation [PMID:39934809]. Loss of PEX11β reduces peroxisome number, elevates oxidative stress, and causes delayed neuronal development and neuronal death [PMID:21954064], and in humans a homozygous nonsense mutation produces an isolated peroxisome division defect that is temperature-sensitive and correlates with PEX11γ levels [PMID:22581968]. PEX11β-dependent peroxisome dynamics also shape membrane lipid composition, as its deficiency decreases DHA-containing and ether-linked phospholipids while raising arachidonic and oleic acid [PMID:36522796, PMID:41756896].","teleology":[{"year":1998,"claim":"Established that PEX11β is not merely associated with proliferating peroxisomes but is itself sufficient to drive their proliferation, defining an ordered elongation-segregation-division mechanism.","evidence":"Overexpression of human PEX11β in mammalian cells with time-course microscopy; Northern blot of rat tissues","pmids":["9792670"],"confidence":"High","gaps":["Did not identify the fission machinery executing the division step","Mechanism of PEX11β segregation from other membrane proteins unresolved","Constitutive expression pattern did not address post-translational control"]},{"year":2011,"claim":"Linked PEX11β loss to a physiological phenotype, showing peroxisome reduction causes oxidative stress and neurodevelopmental failure in vivo.","evidence":"Pex11β knockout and heterozygous mouse models with neuronal cultures, ROS assays, and neuronal marker quantification","pmids":["21954064"],"confidence":"High","gaps":["Did not establish the molecular pathway connecting peroxisome loss to neuronal death","Compensatory SOD2 upregulation mechanism not defined"]},{"year":2012,"claim":"Confirmed in humans that PEX11β specifically controls peroxisome division independent of metabolic functions, and revealed isoform-distinct biochemical membrane properties.","evidence":"Patient fibroblast analysis with Sanger sequencing and temperature-shift experiments; detergent extraction assays comparing PEX11 isoforms","pmids":["22581968","22875152"],"confidence":"Medium","gaps":["Basis of the temperature-sensitive PEX11γ compensation not defined","Structural basis of distinct membrane association of PEX11β unknown"]},{"year":2013,"claim":"Showed in an amphibian ortholog model that PEX11β loss broadly downregulates peroxisomal gene expression and elevates both cellular and mitochondrial ROS, connecting peroxisome dynamics to redox homeostasis.","evidence":"Morpholino knockdown in Xenopus A6 cells with qRT-PCR, immunofluorescence, and ROS assays","pmids":["24234511"],"confidence":"Medium","gaps":["Whether transcriptional changes are direct or secondary to peroxisome loss is unresolved","Mechanism linking peroxisome dysfunction to mitochondrial ROS not defined"]},{"year":2019,"claim":"Tested whether PEX11β governs membrane permeability and instead uncovered a role in correct sorting of peroxisomal proteins.","evidence":"CRISPR-Cas9 knockout in Flp-In T-REx 293 cells with H2O2 permeation assays, immunofluorescence, and subcellular fractionation","pmids":["31129117"],"confidence":"Medium","gaps":["Mechanism of mislocalization to mitochondria not established","Whether sorting defect is direct or a consequence of altered peroxisome dynamics unknown"]},{"year":2020,"claim":"Placed PEX11β downstream of a defined signaling axis by identifying a functional SMAD2/3 site in its promoter and linking TGFβ to PEX11β-dependent elongation.","evidence":"Cell-based proliferation assay, time-resolved mRNA profiling, and promoter analysis with TGFβ treatment","pmids":["33195217"],"confidence":"Medium","gaps":["Full epistasis from TGFβ to elongation not reconstituted","Direct SMAD occupancy of the endogenous promoter not demonstrated"]},{"year":2022,"claim":"Resolved how PEX11β interfaces with the fission machinery, demonstrating a DRP1/FIS1-dependent pathway that operates in parallel to MFF.","evidence":"siRNA/shRNA knockdown of MFF, FIS1, DRP1, patient cells, and mitochondria-targeted PEX11β constructs with live and fixed imaging","pmids":["35678336"],"confidence":"High","gaps":["Direct physical interactions between PEX11β and DRP1/FIS1 not biochemically mapped","How PEX11β recruits or activates the fission apparatus is undefined"]},{"year":2022,"claim":"Identified post-translational destabilization of PEX11β by AKT1 as a regulatory input affecting peroxisome biogenesis and macrophage inflammatory output.","evidence":"ISOC1 knockdown in LPS-treated RAW264.7 macrophages with AKT1 manipulation and PEX11B stability assays","pmids":["36144632"],"confidence":"Low","gaps":["Nature of the AKT1-driven protein modification is not specified","Single cell system; direct AKT1-PEX11β relationship not biochemically confirmed"]},{"year":2022,"claim":"Connected PEX11β-dependent peroxisome dynamics to membrane lipid composition, showing deficiency lowers DHA-containing phospholipids.","evidence":"Lipidomics of PEX11β-deficient patient fibroblasts and Pex11β-KO mouse embryonic fibroblasts","pmids":["36522796"],"confidence":"Medium","gaps":["Whether lipid changes are causal for phenotypes or downstream consequences is unresolved","Enzymatic basis of altered fatty acid composition not defined"]},{"year":2025,"claim":"Defined a direct post-translational switch on PEX11β: palmitoylation at Cys25 disrupts self-interaction and blocks elongation.","evidence":"Acyl-RAC and acyl-biotin exchange assays with C25 site-directed mutagenesis and super-resolution imaging in Schwann cells","pmids":["39934809"],"confidence":"Medium","gaps":["Palmitoyltransferase responsible for C25 modification not identified","Single lab and cell type; in vivo relevance not established"]},{"year":2025,"claim":"Proposed signaling and antiviral roles connecting PEX11β to peroxisome-ER contacts and membrane fluidity, broadening its functional context.","evidence":"PKC/GSK3β pharmacological perturbation with VAPA/VAPB knockdown (preprint); CRISPR screen and viral infection assays in sheep cells (preprint)","pmids":["bio_10.1101_2025.01.21.634043","bio_10.1101_2025.11.28.691156"],"confidence":"Low","gaps":["Preprints, not peer-reviewed","Direct biochemical link between PKC and PEX11β not demonstrated","Antiviral mechanism rests on indirect membrane fluidity readouts"]},{"year":2026,"claim":"Showed in a human iPSC neural model that PEX11β loss specifically impairs peroxisomal fission and fission-protein recruitment, and reduces ether-linked phospholipids, without affecting mitochondria.","evidence":"CRISPR/Cas9 knockout in iPSC-derived neural progenitors with live imaging, lipidomics, and fission protein recruitment assays (preprint)","pmids":["41756896"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism of impaired fission protein recruitment not defined"]},{"year":null,"claim":"How PEX11β physically couples membrane elongation to recruitment of the DRP1/FIS1 fission machinery, and which enzymes deposit and reverse its regulatory modifications, remain unresolved.","evidence":"No direct structural or biochemical interaction mapping in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of PEX11β membrane action","Palmitoyltransferase and AKT1-target residues unidentified","Direct PEX11β-DRP1/FIS1 binding not established"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,1,3,5,12]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,6,12]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O96011","full_name":"Peroxisomal membrane protein 11B","aliases":["Peroxin-11B","Peroxisomal biogenesis factor 11B","Protein PEX11 homolog beta","PEX11-beta"],"length_aa":259,"mass_kda":28.4,"function":"Involved in peroxisomal proliferation (PubMed:9792670). May regulate peroxisome division by recruiting the dynamin-related GTPase DNM1L to the peroxisomal membrane (PubMed:12618434). Promotes membrane protrusion and elongation on the peroxisomal surface (PubMed:20826455)","subcellular_location":"Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/O96011/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEX11B","classification":"Not Classified","n_dependent_lines":115,"n_total_lines":1208,"dependency_fraction":0.09519867549668874},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEX11B","total_profiled":1310},"omim":[{"mim_id":"620805","title":"ISOCHORISMATASE DOMAIN-CONTAINING PROTEIN 1; ISOC1","url":"https://www.omim.org/entry/620805"},{"mim_id":"614920","title":"PEROXISOME BIOGENESIS DISORDER 14B; PEX14B","url":"https://www.omim.org/entry/614920"},{"mim_id":"611748","title":"OTU DOMAIN-CONTAINING PROTEIN 7B; OTUD7B","url":"https://www.omim.org/entry/611748"},{"mim_id":"607583","title":"PEROXISOME BIOGENESIS FACTOR 11G; PEX11G","url":"https://www.omim.org/entry/607583"},{"mim_id":"603867","title":"PEROXISOME BIOGENESIS FACTOR 11B; PEX11B","url":"https://www.omim.org/entry/603867"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PEX11B"},"hgnc":{"alias_symbol":["PEX11beta","PEX11β"],"prev_symbol":[]},"alphafold":{"accession":"O96011","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O96011","model_url":"https://alphafold.ebi.ac.uk/files/AF-O96011-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O96011-F1-predicted_aligned_error_v6.png","plddt_mean":88.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEX11B","jax_strain_url":"https://www.jax.org/strain/search?query=PEX11B"},"sequence":{"accession":"O96011","fasta_url":"https://rest.uniprot.org/uniprotkb/O96011.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O96011/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O96011"}},"corpus_meta":[{"pmid":"9792670","id":"PMC_9792670","title":"Expression of PEX11beta mediates peroxisome proliferation in the absence of extracellular stimuli.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9792670","citation_count":222,"is_preprint":false},{"pmid":"22581968","id":"PMC_22581968","title":"A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22581968","citation_count":107,"is_preprint":false},{"pmid":"21954064","id":"PMC_21954064","title":"Deletion of a single allele of the Pex11β gene is sufficient to cause oxidative stress, delayed differentiation and neuronal death in mouse brain.","date":"2011","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/21954064","citation_count":46,"is_preprint":false},{"pmid":"31129117","id":"PMC_31129117","title":"Deciphering the potential involvement of PXMP2 and PEX11B in hydrogen peroxide permeation across the peroxisomal membrane reveals a role for PEX11B in protein sorting.","date":"2019","source":"Biochimica et biophysica acta. Biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/31129117","citation_count":29,"is_preprint":false},{"pmid":"35678336","id":"PMC_35678336","title":"PEX11β and FIS1 cooperate in peroxisome division independently of mitochondrial fission factor.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/35678336","citation_count":27,"is_preprint":false},{"pmid":"22581969","id":"PMC_22581969","title":"First PEX11β patient extends spectrum of peroxisomal biogenesis disorder phenotypes.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22581969","citation_count":26,"is_preprint":false},{"pmid":"31724321","id":"PMC_31724321","title":"Variant analysis of PEX11B gene from a family with peroxisome biogenesis disorder 14B by whole exome sequencing.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31724321","citation_count":17,"is_preprint":false},{"pmid":"22875152","id":"PMC_22875152","title":"Postfixation detergent treatment liberates the membrane modelling protein Pex11β from peroxisomal membranes.","date":"2012","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22875152","citation_count":14,"is_preprint":false},{"pmid":"36144632","id":"PMC_36144632","title":"ISOC1 Modulates Inflammatory Responses in Macrophages through the AKT1/PEX11B/Peroxisome Pathway.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36144632","citation_count":12,"is_preprint":false},{"pmid":"33195217","id":"PMC_33195217","title":"A Functional SMAD2/3 Binding Site in the PEX11β Promoter Identifies a Role for TGFβ in Peroxisome Proliferation in Humans.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33195217","citation_count":11,"is_preprint":false},{"pmid":"26562432","id":"PMC_26562432","title":"Pioglitazone significantly prevented decreased rate of neural differentiation of mouse embryonic stem cells which was reduced by Pex11β knock-down.","date":"2015","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26562432","citation_count":9,"is_preprint":false},{"pmid":"39934809","id":"PMC_39934809","title":"PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy.","date":"2025","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/39934809","citation_count":8,"is_preprint":false},{"pmid":"33558817","id":"PMC_33558817","title":"A Novel Mutation in PEX11β Gene.","date":"2021","source":"Iranian journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33558817","citation_count":8,"is_preprint":false},{"pmid":"36522796","id":"PMC_36522796","title":"Genetic defects in peroxisome morphogenesis (Pex11β, dynamin-like protein 1, and nucleoside diphosphate kinase 3) affect docosahexaenoic acid-phospholipid metabolism.","date":"2022","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/36522796","citation_count":8,"is_preprint":false},{"pmid":"24234511","id":"PMC_24234511","title":"Knockdown of Pex11β reveals its pivotal role in regulating peroxisomal genes, numbers, and ROS levels in Xenopus laevis A6 cells.","date":"2013","source":"In vitro cellular & developmental biology. 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one","url":"https://pubmed.ncbi.nlm.nih.gov/39652567","citation_count":3,"is_preprint":false},{"pmid":"41756896","id":"PMC_41756896","title":"Modeling the cell biology of PEX11β deficiency during human neurogenesis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41756896","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.24.684183","title":"PEX11β-mediated improvement of mitochondrial dysfunction restores behavioral defect and cellular viability in neuropathological conditions","date":"2025-10-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.24.684183","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.28.691156","title":"Genome-wide CRISPR screen reveals PEX11B as a host restriction factor against ORFV through membrane fluidity regulation","date":"2025-11-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.28.691156","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.21.634043","title":"Protein Kinase C positively regulates peroxisome biogenesis by promoting peroxisome-endoplasmic reticulum interaction","date":"2025-01-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.21.634043","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12301,"output_tokens":3802,"usd":0.046967,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11673,"output_tokens":3878,"usd":0.077658,"stage2_stop_reason":"end_turn"},"total_usd":0.124625,"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\": 1998,\n      \"finding\": \"Overexpression of PEX11β alone is sufficient to induce peroxisome proliferation in the absence of extracellular stimuli, acting through a multistep process involving peroxisome elongation, segregation of PEX11β from other peroxisomal membrane proteins, followed by peroxisome division.\",\n      \"method\": \"Overexpression of human PEX11β in mammalian cells with time-course microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean overexpression with defined morphological phenotype, replicated across multiple studies confirming the elongation-then-division mechanism\",\n      \"pmids\": [\"9792670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PEX11β is a peroxisomal membrane protein whose mRNA levels are similar across all rat tissues examined and are unaffected by peroxisome-proliferating agents, implicating it in constitutive (rather than stimulus-induced) control of peroxisome abundance.\",\n      \"method\": \"Northern blot analysis of rat tissues treated with peroxisome proliferators (clofibrate, DEHP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA quantification in multiple tissues and conditions, single lab\",\n      \"pmids\": [\"9792670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A homozygous nonsense mutation in PEX11β causes an isolated peroxisome division defect without affecting standard peroxisomal metabolic parameters, and the division defect is exacerbated at 40°C correlating with decreased PEX11γ expression.\",\n      \"method\": \"Patient fibroblast biochemical/microscopic analysis, Sanger sequencing of PEX11β, temperature-shift experiments\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in patient cells with defined cellular phenotype, single lab with orthogonal biochemical and microscopy methods\",\n      \"pmids\": [\"22581968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PEX11β, but not PEX11α or PEX11γ, is almost exclusively extracted from peroxisomal membranes of paraformaldehyde-fixed cells by Triton X-100 permeabilization, indicating biochemically distinct membrane association properties of PEX11β compared to other isoforms; loss can be prevented by digitonin permeabilization, glutaraldehyde fixation, or large protein tag (YFP) fusion.\",\n      \"method\": \"Detergent extraction assay (Triton X-100 vs digitonin) on PFA-fixed cells, immunofluorescence, western blot of detergent fractions\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation with orthogonal isoform comparisons, single lab\",\n      \"pmids\": [\"22875152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Deletion of both alleles of Pex11β in mice reduces peroxisome number by ~30%, causes increased oxidative stress, delayed neuronal development, and neuronal death; heterozygous deletion (one allele) slightly increases peroxisome abundance yet also causes oxidative stress and partial neuronal death, with partial compensation via SOD2 upregulation.\",\n      \"method\": \"Pex11β knockout and heterozygous mouse models; primary neuronal cultures; immunofluorescence; mRNA/protein quantification of neuronal markers; ROS assays\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal readouts (peroxisome number, oxidative stress markers, neuronal differentiation markers), replicated in vivo and in vitro\",\n      \"pmids\": [\"21954064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inactivation of PEX11B (via CRISPR-Cas9) does not affect H2O2 permeation across the peroxisomal membrane but unexpectedly leads to partial mislocalization of both peroxisomal membrane and matrix proteins to mitochondria and a decrease in peroxisome density, suggesting a role for PEX11B in peroxisomal protein sorting.\",\n      \"method\": \"CRISPR-Cas9 knockout of PEX11B in Flp-In T-REx 293 cells; controlled intracellular H2O2 generation assay; immunofluorescence and subcellular fractionation\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with orthogonal localization and functional assays, single lab\",\n      \"pmids\": [\"31129117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PEX11β can promote peroxisome division in the absence of MFF (mitochondrial fission factor) through a DRP1- and FIS1-dependent alternative pathway; MFF can restore peroxisome morphology in PEX11β-deficient patient cells independently of PEX11β; targeting PEX11β to mitochondria induces mitochondrial division.\",\n      \"method\": \"siRNA/shRNA knockdown of MFF, FIS1, DRP1; PEX11β-deficient patient cells; mitochondria-targeted PEX11β constructs; live-cell and fixed immunofluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic perturbations (MFF KD, FIS1 KD, DRP1 KD, patient cells) with defined morphological phenotypes and orthogonal targeting experiments, single lab with comprehensive controls\",\n      \"pmids\": [\"35678336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A functional SMAD2/3 binding site is present in the PEX11β promoter; TGFβ signaling induces peroxisome elongation (a prerequisite for proliferation) and correlates with time-resolved upregulation of PEX11β mRNA but not PEX11α or PEX11γ, placing PEX11β downstream of the TGFβ/SMAD2/3 transcriptional axis.\",\n      \"method\": \"Cell-based peroxisome proliferation assay; time-resolved mRNA expression profiling; promoter analysis with SMAD2/3 binding site identification; TGFβ treatment\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional promoter binding site identified, correlative mRNA changes with TGFβ, single lab; functional SMAD binding established but full mechanistic epistasis not completely reconstituted\",\n      \"pmids\": [\"33195217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ISOC1 deficiency activates AKT1, and overactivation of AKT1 reduces the stability of PEX11B through protein modification (post-translational), thereby reducing peroxisome biogenesis and affecting inflammatory cytokine production in macrophages.\",\n      \"method\": \"ISOC1 siRNA knockdown in LPS-treated RAW264.7 macrophages; AKT1 overexpression/inhibition; PEX11B stability assays; cytokine measurement\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell system; the nature of 'protein modification' is not specified in the abstract; limited mechanistic detail\",\n      \"pmids\": [\"36144632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In fibroblasts from patients deficient in PEX11β (as well as DLP1 and NME3), docosahexaenoic acid (DHA)-containing phospholipids are decreased and arachidonic acid/oleic acid levels are elevated, establishing that PEX11β-dependent peroxisome morphology/dynamics affect phospholipid fatty acid composition.\",\n      \"method\": \"Phospholipid composition analysis (lipidomics) of patient fibroblasts (PEX11β-deficient) and Pex11β-KO mouse embryonic fibroblasts\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in patient cells and KO mouse fibroblasts with direct lipid measurement; multiple genetic backgrounds tested\",\n      \"pmids\": [\"36522796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Palmitic acid (PA) induces palmitoylation of PEX11B at the C25 site, which disrupts PEX11B self-interaction and impedes peroxisome elongation, reducing peroxisomal biogenesis in Schwann cells.\",\n      \"method\": \"Acyl-RAC assay and acyl-biotin exchange (ABE) assay for palmitoylation detection; site-directed mutagenesis of C25; laser confocal super-resolution imaging; western blot\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical palmitoylation assays with site-specific mutagenesis and functional readout, single lab\",\n      \"pmids\": [\"39934809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of Pex11β in Xenopus laevis A6 kidney cells decreases mRNA levels of Pex1, PMP70, and PPARγ, reduces PMP70 protein and peroxisome-like structures, and results in increased cellular H2O2 and mitochondrial reactive oxygen species.\",\n      \"method\": \"Morpholino-mediated knockdown; qRT-PCR; immunofluorescence; Amplex Red, DCFDA, and MitoTracker ROS assays\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal readouts in Xenopus ortholog model, single lab\",\n      \"pmids\": [\"24234511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PEX11β knockout in human iPSC-derived neural progenitors causes elongated peroxisomal morphology and reduced peroxisomal fission with impaired recruitment of fission proteins, without affecting mitochondrial morphology or respiration; lipidomic analysis showed reduced ether-linked phospholipids in PEX11β-deficient neural progenitors; elongated peroxisomal morphology was independent of the peroxisome-endoplasmic reticulum tether.\",\n      \"method\": \"CRISPR/Cas9 knockout of PEX11β in human iPSCs differentiated to neural progenitors and neural rosettes; live imaging; lipidomics; fission protein recruitment assays; mitochondrial respiration measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous KO with multiple orthogonal methods in human iPSC-derived model; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41756896\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKC activation promotes PEX11β-dependent peroxisome formation through inactivation of GSK3β, which promotes peroxisome-ER contact site formation; removal of VAPA and VAPB impairs PEX11β-dependent peroxisome biogenesis and PKC regulation.\",\n      \"method\": \"PKC activator/inhibitor treatment; GSK3β inhibition; VAPA/VAPB knockdown; live-cell imaging of peroxisome numbers; peroxisome-ER contact site assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, pathway placement based on pharmacological perturbations without direct biochemical interaction between PKC and PEX11β demonstrated\",\n      \"pmids\": [\"bio_10.1101_2025.01.21.634043\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PEX11B knockout in sheep OA3.Ts cells increases susceptibility to orf virus (ORFV) infection; mechanistically, PEX11B loss disrupts peroxisomal integrity and lipid metabolism, leading to increased plasma membrane fluidity that promotes viral entry and replication.\",\n      \"method\": \"Genome-wide CRISPR knockout screen in sheep OA3.Ts cells; PEX11B KO validation; viral infection assays; membrane fluidity measurements; lipid metabolism analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, novel antiviral function with mechanistic link through membrane fluidity but limited biochemical detail in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.11.28.691156\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PEX11β is a peroxisomal membrane protein that drives peroxisome proliferation by initiating membrane elongation, segregating from other peroxisomal membrane proteins, and then cooperating with DRP1/FIS1 (and in parallel with MFF) to execute fission; its activity is regulated at the transcriptional level by TGFβ/SMAD2/3 signaling and post-translationally by AKT1-mediated destabilization and palmitoylation at C25 (which disrupts self-interaction and blocks elongation), while its loss impairs DHA-containing phospholipid metabolism, increases oxidative stress, and causes neurodevelopmental defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PEX11β is a peroxisomal membrane protein that functions as the master driver of peroxisome proliferation, and its overexpression alone is sufficient to induce proliferation through an ordered multistep program of membrane elongation, segregation of PEX11β from other peroxisomal membrane proteins, and subsequent division [#0]. Unlike inducible isoforms, PEX11β is expressed constitutively across tissues and is insensitive to peroxisome-proliferating agents, marking it as the basal regulator of peroxisome abundance [#1]; it also possesses biochemically distinct membrane-association properties relative to PEX11α and PEX11γ [#3]. PEX11β initiates the elongation step and then cooperates with the fission machinery—DRP1 and FIS1—to execute division, operating in parallel to MFF such that it can drive division even when MFF is absent [#6]. Its proliferative activity is gated transcriptionally downstream of TGFβ/SMAD2/3 signaling via a functional SMAD2/3 site in the PEX11β promoter [#7], and post-translationally by palmitoylation at Cys25, which disrupts PEX11β self-interaction and blocks elongation [#10]. Loss of PEX11β reduces peroxisome number, elevates oxidative stress, and causes delayed neuronal development and neuronal death [#4], and in humans a homozygous nonsense mutation produces an isolated peroxisome division defect that is temperature-sensitive and correlates with PEX11γ levels [#2]. PEX11β-dependent peroxisome dynamics also shape membrane lipid composition, as its deficiency decreases DHA-containing and ether-linked phospholipids while raising arachidonic and oleic acid [#9, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that PEX11β is not merely associated with proliferating peroxisomes but is itself sufficient to drive their proliferation, defining an ordered elongation-segregation-division mechanism.\",\n      \"evidence\": \"Overexpression of human PEX11β in mammalian cells with time-course microscopy; Northern blot of rat tissues\",\n      \"pmids\": [\"9792670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not identify the fission machinery executing the division step\",\n        \"Mechanism of PEX11β segregation from other membrane proteins unresolved\",\n        \"Constitutive expression pattern did not address post-translational control\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked PEX11β loss to a physiological phenotype, showing peroxisome reduction causes oxidative stress and neurodevelopmental failure in vivo.\",\n      \"evidence\": \"Pex11β knockout and heterozygous mouse models with neuronal cultures, ROS assays, and neuronal marker quantification\",\n      \"pmids\": [\"21954064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not establish the molecular pathway connecting peroxisome loss to neuronal death\",\n        \"Compensatory SOD2 upregulation mechanism not defined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed in humans that PEX11β specifically controls peroxisome division independent of metabolic functions, and revealed isoform-distinct biochemical membrane properties.\",\n      \"evidence\": \"Patient fibroblast analysis with Sanger sequencing and temperature-shift experiments; detergent extraction assays comparing PEX11 isoforms\",\n      \"pmids\": [\"22581968\", \"22875152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Basis of the temperature-sensitive PEX11γ compensation not defined\",\n        \"Structural basis of distinct membrane association of PEX11β unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed in an amphibian ortholog model that PEX11β loss broadly downregulates peroxisomal gene expression and elevates both cellular and mitochondrial ROS, connecting peroxisome dynamics to redox homeostasis.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus A6 cells with qRT-PCR, immunofluorescence, and ROS assays\",\n      \"pmids\": [\"24234511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether transcriptional changes are direct or secondary to peroxisome loss is unresolved\",\n        \"Mechanism linking peroxisome dysfunction to mitochondrial ROS not defined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested whether PEX11β governs membrane permeability and instead uncovered a role in correct sorting of peroxisomal proteins.\",\n      \"evidence\": \"CRISPR-Cas9 knockout in Flp-In T-REx 293 cells with H2O2 permeation assays, immunofluorescence, and subcellular fractionation\",\n      \"pmids\": [\"31129117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of mislocalization to mitochondria not established\",\n        \"Whether sorting defect is direct or a consequence of altered peroxisome dynamics unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed PEX11β downstream of a defined signaling axis by identifying a functional SMAD2/3 site in its promoter and linking TGFβ to PEX11β-dependent elongation.\",\n      \"evidence\": \"Cell-based proliferation assay, time-resolved mRNA profiling, and promoter analysis with TGFβ treatment\",\n      \"pmids\": [\"33195217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Full epistasis from TGFβ to elongation not reconstituted\",\n        \"Direct SMAD occupancy of the endogenous promoter not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how PEX11β interfaces with the fission machinery, demonstrating a DRP1/FIS1-dependent pathway that operates in parallel to MFF.\",\n      \"evidence\": \"siRNA/shRNA knockdown of MFF, FIS1, DRP1, patient cells, and mitochondria-targeted PEX11β constructs with live and fixed imaging\",\n      \"pmids\": [\"35678336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct physical interactions between PEX11β and DRP1/FIS1 not biochemically mapped\",\n        \"How PEX11β recruits or activates the fission apparatus is undefined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-translational destabilization of PEX11β by AKT1 as a regulatory input affecting peroxisome biogenesis and macrophage inflammatory output.\",\n      \"evidence\": \"ISOC1 knockdown in LPS-treated RAW264.7 macrophages with AKT1 manipulation and PEX11B stability assays\",\n      \"pmids\": [\"36144632\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Nature of the AKT1-driven protein modification is not specified\",\n        \"Single cell system; direct AKT1-PEX11β relationship not biochemically confirmed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PEX11β-dependent peroxisome dynamics to membrane lipid composition, showing deficiency lowers DHA-containing phospholipids.\",\n      \"evidence\": \"Lipidomics of PEX11β-deficient patient fibroblasts and Pex11β-KO mouse embryonic fibroblasts\",\n      \"pmids\": [\"36522796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether lipid changes are causal for phenotypes or downstream consequences is unresolved\",\n        \"Enzymatic basis of altered fatty acid composition not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a direct post-translational switch on PEX11β: palmitoylation at Cys25 disrupts self-interaction and blocks elongation.\",\n      \"evidence\": \"Acyl-RAC and acyl-biotin exchange assays with C25 site-directed mutagenesis and super-resolution imaging in Schwann cells\",\n      \"pmids\": [\"39934809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Palmitoyltransferase responsible for C25 modification not identified\",\n        \"Single lab and cell type; in vivo relevance not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed signaling and antiviral roles connecting PEX11β to peroxisome-ER contacts and membrane fluidity, broadening its functional context.\",\n      \"evidence\": \"PKC/GSK3β pharmacological perturbation with VAPA/VAPB knockdown (preprint); CRISPR screen and viral infection assays in sheep cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.21.634043\", \"bio_10.1101_2025.11.28.691156\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprints, not peer-reviewed\",\n        \"Direct biochemical link between PKC and PEX11β not demonstrated\",\n        \"Antiviral mechanism rests on indirect membrane fluidity readouts\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed in a human iPSC neural model that PEX11β loss specifically impairs peroxisomal fission and fission-protein recruitment, and reduces ether-linked phospholipids, without affecting mitochondria.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in iPSC-derived neural progenitors with live imaging, lipidomics, and fission protein recruitment assays (preprint)\",\n      \"pmids\": [\"41756896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Mechanism of impaired fission protein recruitment not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PEX11β physically couples membrane elongation to recruitment of the DRP1/FIS1 fission machinery, and which enzymes deposit and reverse its regulatory modifications, remain unresolved.\",\n      \"evidence\": \"No direct structural or biochemical interaction mapping in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PEX11β membrane action\",\n        \"Palmitoyltransferase and AKT1-target residues unidentified\",\n        \"Direct PEX11β-DRP1/FIS1 binding not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 1, 3, 5, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}