{"gene":"PHB1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2002,"finding":"PHB1 (Phb1p) and PHB2 (Phb2p) localize to the mitochondrial inner membrane where they form a large multimeric ring complex (~12-14 copies of each subunit) that acts as a membrane-bound chaperone, directly binding newly synthesized mitochondrial translation products and stabilizing them against degradation by membrane-bound AAA metalloproteases.","method":"Biochemical fractionation, native molecular weight analysis, direct binding assays with mitochondrial translation products","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated findings from multiple labs reviewed here; direct binding and fractionation experiments establishing inner membrane localization and chaperone function for respiratory complex subunit assembly","pmids":["11852914"],"is_preprint":false},{"year":2007,"finding":"In human T cells, PHB1 and PHB2 localize to the mitochondrial inner membrane (not the nucleus); PHB1 is serine-phosphorylated and PHB2 is serine- and tyrosine-phosphorylated (Tyr248 mapped by MS and confirmed by mutagenesis). siRNA-mediated knockdown of PHBs disrupts mitochondrial membrane potential, establishing a role for the PHB1/PHB2 phosphocomplex in mitochondrial homeostasis and T cell survival.","method":"Subcellular fractionation, immunofluorescence, electron microscopy, orthophosphate labeling, phosphoamino acid analysis, mass spectrometry, site-directed mutagenesis, phosphospecific antibodies, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, EM, MS, mutagenesis, siRNA) in single rigorous study establishing localization, phosphorylation sites, and functional consequence","pmids":["18086671"],"is_preprint":false},{"year":2016,"finding":"In human ESCs, PHB forms a protein complex with HIRA (a histone H3.3 chaperone), stabilizes HIRA complex components, and together with HIRA controls global deposition of histone H3.3 and gene expression. PHB and HIRA regulate chromatin architecture at isocitrate dehydrogenase gene promoters to promote transcription and α-ketoglutarate production. Genome-wide siRNA screening identified PHB as essential for hESC self-renewal.","method":"Genome-wide siRNA screen, co-immunoprecipitation, chromatin assays, gene expression analysis, metabolite measurement","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen identification plus reciprocal co-IP, chromatin, and metabolic readouts in single study establishing nuclear PHB-HIRA complex function","pmids":["27939217"],"is_preprint":false},{"year":2017,"finding":"PHB complex deficiency impairs the formation of mitochondrial respiratory supercomplexes (RSCs) without altering the abundance of individual respiratory complex subunits, leading to elevated basal mitochondrial ROS production and increased mitoflash frequency. Co-expression of PHB1 and PHB2 rescues these defects, indicating the multimeric PHB complex is the functional unit for RSC assembly.","method":"siRNA knockdown, live-cell mitoflash imaging, ROS measurement, blue native PAGE for RSC analysis, rescue by co-expression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined molecular phenotype (RSC loss), rescue experiment, and multiple orthogonal readouts in single study","pmids":["28630166"],"is_preprint":false},{"year":2019,"finding":"TRIM21 acts as an E3 ubiquitin ligase that ubiquitinates PHB1, targeting it for degradation. LPLUNC1 stabilizes PHB1 by competitively impeding the PHB1-TRIM21 interaction (due to stronger binding affinity of LPLUNC1 to PHB1), thus inhibiting PHB1 ubiquitination. PHB1 suppresses NF-κB activity in nasopharyngeal carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assays, competitive binding assays, PHB1 knockdown/overexpression, NF-κB reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assays establish TRIM21 as E3 ligase for PHB1; competitive binding mechanism supported; single lab","pmids":["30886235"],"is_preprint":false},{"year":2013,"finding":"PHB overexpression in undifferentiated rat granulosa cells inhibits apoptosis by increasing anti-apoptotic proteins Bcl-2 and Bcl-xL, reducing cytochrome c release from mitochondria, and inhibiting caspase-3 activity via a PHB→MEK-ERK1/2→Bcl-2/Bcl-xL pathway. PHB silencing fragmented mitochondrial morphology and sensitized cells to apoptosis.","method":"Microarray, immunoblot, adenoviral overexpression and siRNA knockdown, mitochondrial morphology imaging, caspase activity assay, cytochrome c release measurement","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple downstream readouts; pathway placement via Bcl-2 family and ERK; single lab","pmids":["24096434"],"is_preprint":false},{"year":2011,"finding":"PHB overexpression in rat granulosa cells increases mitochondrial PHB content and delays ceramide-induced apoptosis, while adenoviral shRNA silencing of PHB sensitizes cells to ceramide-induced apoptosis. Exogenous ceramide augments mitochondrial PHB expression and causes cytochrome c release and caspase-3 activation, establishing mitochondrial PHB as a critical survival factor in granulosa cells.","method":"Adenoviral overexpression and shRNA knockdown, ceramide treatment, cytochrome c release assay, caspase-3 activation measurement","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with defined apoptotic readouts; single lab; supports prior findings","pmids":["21763324"],"is_preprint":false},{"year":2019,"finding":"FoxM1 binds the PHB1 promoter and enhances PHB1 expression at transcriptional and post-transcriptional levels. PHB1 interacts with C-RAF and promotes ERK1/2 phosphorylation, contributing to paclitaxel resistance. Knockdown of PHB1 sensitizes pancreatic cancer cells to paclitaxel, and FoxM1 inhibition decreases PHB1, p-ERK1/2, and ABCA2 expression.","method":"Promoter binding assay (bioinformatics + reporter), co-immunoprecipitation (PHB1/C-RAF), gene knockdown, phospho-ERK Western blot, in vitro and in vivo paclitaxel resistance assays","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishes PHB1/C-RAF interaction; promoter binding and functional resistance assays; single lab","pmids":["31334335"],"is_preprint":false},{"year":2020,"finding":"PHB in spermatocytes regulates expression of STAG3 (a meiotic cohesin complex component) via a non-canonical JAK2/STAT pathway. The PHB/JAK2 axis modulates histone H3 tyrosine 41 phosphorylation (H3Y41ph) and H3K9me3 at the Stag3 locus. Loss of PHB in male germ cells (Phb-cKO) causes meiotic pachytene arrest, impaired DSB repair, and complete male infertility, also associated with mitochondrial dysfunction.","method":"Conditional knockout mouse (Phb-cKO), meiotic staging, immunofluorescence, ChIP (H3Y41ph, H3K9me3 at Stag3 locus), Western blot for JAK2/STAT pathway components, STAG3 expression analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with defined meiotic phenotype, ChIP-based epigenetic mechanism, and pathway placement via JAK2 axis; multiple orthogonal methods","pmids":["32232334"],"is_preprint":false},{"year":2022,"finding":"CHCHD10 interacts with SLP2 (Stomatin-Like Protein 2) and participates in stabilizing the prohibitin complex in the mitochondrial inner membrane. The ALS/FTD-linked CHCHD10(S59L) variant causes SLP2-prohibitin aggregates and instability of the PHB complex, leading to OMA1 cascade activation, OPA1 processing, mitochondrial fragmentation, abnormal cristae morphogenesis, and motor neuron death. PHB complex destabilization disrupts the mitochondrial contact site and cristae organizing system (MICOS) complex, likely via disruption of OPA1-mitofilin interaction.","method":"Patient fibroblasts, mouse model (Chchd10S59L/+), co-immunoprecipitation, immunofluorescence, spinal cord histology, mitochondrial morphology analysis","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient fibroblasts and mouse model with reciprocal co-IP and defined in vivo pathological phenotype; multiple orthogonal methods","pmids":["35656794"],"is_preprint":false},{"year":2018,"finding":"FL3 (a flavagline) inhibits the interaction between Akt and PHB1 and inhibits Akt-mediated PHB1 phosphorylation, which decreases PHB1 localization to mitochondria. This activates the GADD45α pathway leading to G2/M cell cycle arrest in bladder carcinoma cells. Knockdown of PHB1 mimics FL3-induced cell cycle inhibition, and knockdown of GADD45α rescues the inhibitory effect of FL3.","method":"Co-immunoprecipitation (Akt-PHB interaction), phosphorylation assays, subcellular fractionation, mRNA microarray, PHB1 knockdown, GADD45α knockdown, in vitro and in vivo proliferation assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishes Akt-PHB interaction; fractionation shows localization change; epistasis via GADD45α knockdown; single lab","pmids":["29415747"],"is_preprint":false},{"year":2021,"finding":"STOML2 interacts with PHB (PHB1) as demonstrated by yeast two-hybrid screening and confirmed by co-immunoprecipitation and co-localization in cell lines and tissues. Both STOML2 and PHB activate the MAPK signaling pathway (RAF1-MEK1/2-ERK1/2 phosphorylation) to promote colorectal cancer proliferation.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, STOML2 knockdown, MAPK pathway Western blot","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP confirms interaction; pathway activation by Western blot; single lab","pmids":["34781982"],"is_preprint":false},{"year":2023,"finding":"PHB1 knockdown increases cytoplasmic mtDNA levels and enhances NLRP3 inflammasome activation. Mitophagy inhibitor treatment abolishes PHB1 knockdown-mediated NLRP3 activation, establishing that PHB1 inhibits NLRP3 inflammasome activation through promoting mitophagy.","method":"PHB1 siRNA knockdown, mtDNA cytoplasmic measurement, NLRP3 inflammasome activation assays, mitophagy inhibitor treatment","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype and pharmacological epistasis establishing mitophagy-dependent mechanism; single lab","pmids":["37359543"],"is_preprint":false},{"year":2020,"finding":"PHB interacts with AKT in the mitochondrial sheath of sperm, forming a complex with phospho-PHB (pT258) and phospho-AKT. Blocking PI3K/AKT activity with wortmannin decreases PHB phosphorylation at T258 and reduces sperm motility. Infertile asthenospermic men show reduced phospho-PI3K, phospho-AKT, and phospho-PHB (pT258) levels, suggesting AKT-mediated PHB phosphorylation at T258 regulates sperm motility.","method":"Co-localization microscopy, co-immunoprecipitation, pharmacological inhibition (wortmannin), phosphospecific antibodies, human sperm analysis","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishes PHB-AKT interaction in mitochondria; pharmacological epistasis links AKT to PHB phosphorylation and motility; single lab","pmids":["32859869"],"is_preprint":false},{"year":2020,"finding":"HDAC6 downregulates PHB1 expression and function, impairing PHB1-mediated mitochondrial respiratory chain function, increasing oxidant production and oxidative stress, thereby promoting sepsis development. Inhibition of HDAC6 attenuates CLP-induced sepsis through restoration of mitochondrial function.","method":"CLP rat sepsis model, HDAC6 inhibition, RT-PCR, Western blot, mitochondrial respiratory control rate measurement","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Western blot and functional respiratory rate measurement; mechanism of HDAC6 regulation of PHB1 not directly demonstrated at molecular level","pmids":["32221047"],"is_preprint":false},{"year":2022,"finding":"Arctigenin elevates PHB1 protein levels by blocking TRIM21-mediated ubiquitination of PHB1 via estrogen receptor β (ERβ)-dependent competitive interaction: ERβ activation allows it to competitively bind PHB1 and disrupt the TRIM21-PHB1 interaction, preventing PHB1 ubiquitination-mediated degradation and inhibiting mitochondrial apoptosis in goblet cells.","method":"In vitro and in vivo colitis models, ERβ knockdown in mice, co-immunoprecipitation (ERβ-PHB1, TRIM21-PHB1), ubiquitination assays, Western blot","journal":"Phytotherapy research : PTR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assays establish competitive binding mechanism; in vivo ERβ knockdown epistasis; single lab; corroborates TRIM21-PHB1 interaction from prior work","pmids":["35599350"],"is_preprint":false},{"year":2023,"finding":"PHB1 (prohibitin) binds to β-catenin and stabilizes it by inhibiting ubiquitin-mediated degradation, thereby increasing Wnt/β-catenin signaling activity and promoting bladder cancer cell EMT, migration, invasion, and metastasis. β-catenin knockdown reduces cancer cell migration and invasion in PHB1-overexpressing cells.","method":"Co-immunoprecipitation, immunofluorescence, gene knockdown/overexpression, transwell/wound-healing assays, in vivo lung metastasis nude mouse model, Western blot","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishes PHB1-β-catenin interaction; epistasis via β-catenin KD; in vivo validation; single lab","pmids":["37235908"],"is_preprint":false},{"year":2024,"finding":"PHB1 interacts with Sam50 (a mitochondrial outer membrane protein) and together they stabilize mtDNA. Lycopene protects against atrazine-induced kidney damage by interacting with Sam50/PHB1 to prevent mtDNA instability, cytoplasmic mtDNA release, and downstream cGAS-STING pathway activation leading to PANoptosis.","method":"In vivo mouse model (atrazine + lycopene), Sam50/PHB1 interaction assays, mtDNA stability measurement, mPTP and BAX pore assays, cGAS-STING pathway analysis","journal":"Journal of agricultural and food chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction assays described but abstract lacks detail on direct binding method; single lab; mechanistic chain proposed with limited molecular resolution in abstract","pmids":["38820047"],"is_preprint":false},{"year":2024,"finding":"In Saccharomyces cerevisiae, both Phb1 and Phb2 (orthologs of human PHB1/PHB2) function as Atg8 receptors to support mitophagy via conserved AIM/LIR-like motifs. Phb1 and Phb2 interact with and co-localize with Atg8 at mitochondria. The prohibitin complex also negatively regulates Atg32 processing: in the absence of prohibitins, Atg32 C-terminal processing is enhanced in a manner dependent on the rhomboid protease Pcp1 (and the i-AAA protease Yme1).","method":"Yeast Phb1/Phb2 deletion mutants, mitophagy assays, co-immunoprecipitation (Phb1/Phb2 with Atg8), AIM/LIR motif mutagenesis, Atg32 processing assays, genetic epistasis (Yme1, Pcp1 deletion)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, mutagenesis of AIM/LIR motif, genetic epistasis) establishing novel receptor function for mitophagy in yeast orthologs; consistent with mammalian PHB2 mitophagy role","pmids":["38964378"],"is_preprint":false},{"year":2023,"finding":"PHBs (PHB1 and PHB2) are directly associated with the eukaryotic initiation factor 4F (eIF4F) translation complex in CLL cells, as shown by multiomics and knockdown experiments. PHB knockdown mimics treatment with the PHB-binding drug FL3, inhibiting MYC oncogene translation and reducing translation of cell cycle and metabolic proteins. The RAS-RAF-(PHB)-MAPK pathway is not implicated in translation regulation in CLL (negative finding in this context).","method":"Multiomics (proteomics/transcriptomics), PHB knockdown, FL3 pharmacological inhibition, ribosome profiling/translation assays, in vivo CLL mouse model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiomics plus knockdown phenocopy of drug; direct PHB-eIF4F association established; single lab but multiple orthogonal methods","pmids":["37084385"],"is_preprint":false}],"current_model":"PHB1 (prohibitin 1) is a mitochondrial inner membrane scaffold protein that, together with PHB2, forms a large multimeric ring complex acting as a membrane-bound chaperone for respiratory complex assembly, stabilizes respiratory supercomplexes, maintains mitochondrial membrane potential and cristae integrity, and undergoes AKT-mediated phosphorylation; it also functions in the nucleus (complexed with HIRA to regulate histone H3.3 deposition and metabolic gene expression), undergoes TRIM21-mediated ubiquitination (counteracted by LPLUNC1 or ERβ), interacts with C-RAF/ERK and β-catenin signaling, acts as an Atg8/LC3-interacting receptor for mitophagy via AIM/LIR motifs, and directly associates with the eIF4F translation initiation complex to regulate oncogene translation."},"narrative":{"mechanistic_narrative":"PHB1 (prohibitin 1) is a multifunctional scaffold protein best characterized as a mitochondrial inner-membrane chaperone that, with PHB2, assembles into a large multimeric ring complex (~12–14 copies of each subunit) which binds newly synthesized mitochondrial translation products and protects them from membrane-bound AAA proteases [PMID:11852914]. Through this scaffold the PHB complex stabilizes respiratory supercomplex assembly without changing individual complex subunit abundance, limiting basal ROS production and preserving mitochondrial membrane potential [PMID:18086671, PMID:28630166]. The complex is itself stabilized in the inner membrane through associations with SLP2/STOML2 and CHCHD10, and its destabilization disrupts cristae organization (MICOS) and triggers the OMA1–OPA1 fragmentation cascade [PMID:35656794, PMID:34781982]. Beyond bioenergetics, PHB1 supports mitochondrial quality control: in yeast orthologs the prohibitin subunits act as Atg8/LC3 receptors driving mitophagy via AIM/LIR motifs and restrain Atg32 processing [PMID:38964378], and in mammalian cells PHB1 promotes mitophagy to clear damaged mtDNA and thereby limit NLRP3 inflammasome activation [PMID:37359543]. PHB1 also operates outside mitochondria, forming a nuclear complex with the histone H3.3 chaperone HIRA to control H3.3 deposition, isocitrate dehydrogenase gene transcription, and α-ketoglutarate production required for ESC self-renewal [PMID:27939217], and regulating meiotic STAG3 expression through a JAK2/STAT-dependent histone modification pathway essential for male fertility [PMID:32232334]. PHB1 abundance is set by TRIM21-mediated ubiquitination and degradation, which is competitively blocked by LPLUNC1 or ERβ [PMID:30886235, PMID:35599350], and its activity is modulated by AKT-mediated phosphorylation that controls its mitochondrial localization [PMID:29415747, PMID:32859869]. In cancer contexts PHB1 scaffolds C-RAF/STOML2-driven ERK/MAPK signaling, stabilizes β-catenin to drive Wnt signaling and EMT, and associates with the eIF4F initiation complex to promote oncogene (MYC) translation [PMID:31334335, PMID:34781982, PMID:37235908, PMID:37084385].","teleology":[{"year":2002,"claim":"Established the founding molecular function of PHB1: that it and PHB2 form a ring-shaped membrane-bound chaperone protecting nascent mitochondrial translation products from proteolysis.","evidence":"Biochemical fractionation, native molecular weight analysis, and direct binding to mitochondrial translation products","pmids":["11852914"],"confidence":"High","gaps":["Structural basis of the ring assembly not resolved","Did not address non-mitochondrial functions"]},{"year":2007,"claim":"Resolved where PHB1 acts in human cells and that it is post-translationally modified, linking the phosphorylated PHB1/PHB2 complex to membrane potential and cell survival.","evidence":"Subcellular fractionation, EM, MS phosphosite mapping, mutagenesis, and siRNA knockdown in human T cells","pmids":["18086671"],"confidence":"High","gaps":["Kinase responsible for PHB1 serine phosphorylation not identified","Functional role of specific PHB1 phosphosites unresolved"]},{"year":2016,"claim":"Defined a distinct nuclear function for PHB1 as a HIRA partner coupling histone H3.3 deposition to metabolic gene expression and stem cell self-renewal.","evidence":"Genome-wide siRNA screen, reciprocal co-IP, chromatin assays, and metabolite measurement in human ESCs","pmids":["27939217"],"confidence":"High","gaps":["How PHB1 partitions between mitochondria and nucleus unknown","Direct DNA/chromatin contact by PHB1 not shown"]},{"year":2017,"claim":"Showed the functional consequence of PHB chaperone activity is respiratory supercomplex assembly, distinguishing assembly from subunit abundance.","evidence":"siRNA knockdown, blue native PAGE, mitoflash imaging, ROS measurement, and co-expression rescue","pmids":["28630166"],"confidence":"High","gaps":["Direct contacts between PHB ring and supercomplex subunits not mapped"]},{"year":2020,"claim":"Demonstrated that PHB1 controls meiotic progression in vivo by regulating cohesin (STAG3) through a non-canonical JAK2/STAT–histone modification axis.","evidence":"Conditional knockout mouse, meiotic staging, ChIP for H3Y41ph/H3K9me3 at the Stag3 locus, pathway Western blots","pmids":["32232334"],"confidence":"High","gaps":["Whether PHB1 directly engages JAK2 vs. acts indirectly unclear","Relative contribution of mitochondrial vs. epigenetic roles to infertility not separated"]},{"year":2022,"claim":"Placed the PHB complex within the inner-membrane organizing network, showing its stability depends on SLP2/CHCHD10 and its loss collapses cristae via OMA1–OPA1 and MICOS disruption.","evidence":"Patient fibroblasts and CHCHD10(S59L) mouse model with reciprocal co-IP and morphology analysis","pmids":["35656794"],"confidence":"High","gaps":["Direct PHB1–OPA1/mitofilin contacts inferred rather than proven","Stoichiometry of SLP2–PHB assembly not defined"]},{"year":2024,"claim":"Identified prohibitins as direct Atg8/LC3 mitophagy receptors via AIM/LIR motifs and as negative regulators of Atg32 processing, defining a quality-control function.","evidence":"Yeast deletion mutants, co-IP with Atg8, AIM/LIR mutagenesis, and genetic epistasis with Yme1/Pcp1","pmids":["38964378"],"confidence":"High","gaps":["Demonstrated in yeast orthologs; mammalian PHB1 LIR-dependent receptor role not directly tested here"]},{"year":2023,"claim":"Linked PHB1-driven mitophagy to innate immune control by showing it limits cytoplasmic mtDNA accumulation and NLRP3 inflammasome activation.","evidence":"siRNA knockdown, cytoplasmic mtDNA quantification, NLRP3 activation assays, and mitophagy inhibitor epistasis","pmids":["37359543"],"confidence":"Medium","gaps":["Single loss-of-function study","Whether PHB1 acts as the receptor in this mammalian mitophagy not shown directly"]},{"year":2019,"claim":"Established TRIM21 as the E3 ligase setting PHB1 abundance and LPLUNC1 as a competitive stabilizer, defining how PHB1 levels are controlled.","evidence":"Co-IP, ubiquitination and competitive binding assays, knockdown/overexpression, and NF-κB reporters in nasopharyngeal carcinoma","pmids":["30886235"],"confidence":"Medium","gaps":["TRIM21 ubiquitination site on PHB1 not mapped","Single lab"]},{"year":2022,"claim":"Extended the TRIM21 degradation axis by showing ERβ competitively protects PHB1, corroborating the regulated-degradation model in a second disease context.","evidence":"Colitis models, ERβ knockdown in mice, co-IP and ubiquitination assays","pmids":["35599350"],"confidence":"Medium","gaps":["Direct ERβ–PHB1 binding interface not defined","Single lab"]},{"year":2018,"claim":"Showed AKT-mediated phosphorylation governs PHB1 mitochondrial localization and downstream proliferation control via GADD45α.","evidence":"Co-IP, phosphorylation assays, fractionation, microarray, and GADD45α knockdown epistasis in bladder carcinoma","pmids":["29415747"],"confidence":"Medium","gaps":["AKT phosphosite on PHB1 not mapped in this study","Single lab"]},{"year":2020,"claim":"Mapped a specific AKT phosphosite (T258) on PHB1 in sperm and connected PI3K/AKT–PHB1 signaling to motility and human asthenospermia.","evidence":"Co-localization, co-IP, wortmannin inhibition, phosphospecific antibodies, and human sperm analysis","pmids":["32859869"],"confidence":"Medium","gaps":["Functional readout correlative in human samples","Single lab"]},{"year":2021,"claim":"Identified STOML2 as a direct PHB1 partner that co-activates RAF1–MEK–ERK signaling to promote proliferation.","evidence":"Yeast two-hybrid, co-IP, co-localization, knockdown, and MAPK Western blots in colorectal cancer","pmids":["34781982"],"confidence":"Medium","gaps":["Whether STOML2–PHB1 acts via mitochondrial or cytosolic pool unclear","Single lab"]},{"year":2023,"claim":"Defined two additional pro-oncogenic mechanisms: PHB1 stabilization of β-catenin driving Wnt/EMT, and direct PHB association with eIF4F to promote MYC translation.","evidence":"Co-IP, knockdown/overexpression, migration/metastasis assays (β-catenin); multiomics, knockdown, and FL3 phenocopy with ribosome profiling (eIF4F)","pmids":["37235908","37084385"],"confidence":"Medium","gaps":["Direct vs. scaffold-mediated PHB1–eIF4F binding not fully resolved","RAS-RAF-MAPK explicitly not implicated in CLL translation control"]},{"year":null,"claim":"How PHB1 is partitioned among mitochondrial, nuclear, cytosolic and translational pools, and how a single ring chaperone is repurposed for chromatin, signaling and translation roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking the inner-membrane ring to extra-mitochondrial functions","Trafficking/targeting signals directing PHB1 to nucleus or eIF4F not identified","Phosphorylation/ubiquitination code coordinating the multiple pools not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,8]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18,12]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]}],"complexes":["PHB1/PHB2 ring complex","PHB-HIRA complex","SLP2-prohibitin complex","eIF4F complex"],"partners":["PHB2","HIRA","TRIM21","STOML2","CHCHD10","CRAF","AKT","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35232","full_name":"Prohibitin 1","aliases":[],"length_aa":272,"mass_kda":29.8,"function":"Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors in the nucleus (PubMed:11302691, PubMed:20959514, PubMed:28017329, PubMed:31522117). Plays a role in adipose tissue and glucose homeostasis in a sex-specific manner (By similarity). Contributes to pulmonary vascular remodeling by accelerating proliferation of pulmonary arterial smooth muscle cells (By similarity) In the mitochondria, together with PHB2, forms large ring complexes (prohibitin complexes) in the inner mitochondrial membrane (IMM) and functions as a chaperone protein that stabilizes mitochondrial respiratory enzymes and maintains mitochondrial integrity in the IMM, which is required for mitochondrial morphogenesis, neuronal survival, and normal lifespan (Probable). The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner (By similarity). Regulates mitochondrial respiration activity playing a role in cellular aging (PubMed:11302691). The prohibitin complex plays a role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (PubMed:28017329). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117) In the nucleus, acts as a transcription coregulator, enhances promoter binding by TP53, a transcription factor it activates, but reduces the promoter binding by E2F1, a transcription factor it represses (PubMed:14500729). Interacts with STAT3 to affect IL17 secretion in T-helper Th17 cells (PubMed:31899195) In the plasma membrane, cooperates with CD86 to mediate CD86-signaling in B lymphocytes that regulates the level of IgG1 produced through the activation of distal signaling intermediates (By similarity). Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity)","subcellular_location":"Mitochondrion inner membrane; Nucleus; Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P35232/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PHB1","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHB1","total_profiled":1310},"omim":[{"mim_id":"617081","title":"OMA1 ZINC METALLOPEPTIDASE; OMA1","url":"https://www.omim.org/entry/617081"},{"mim_id":"614461","title":"UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX ASSEMBLY FACTOR 2; UQCC2","url":"https://www.omim.org/entry/614461"},{"mim_id":"610704","title":"PROHIBITIN 2; PHB2","url":"https://www.omim.org/entry/610704"},{"mim_id":"608292","title":"STOMATIN-LIKE PROTEIN 2; STOML2","url":"https://www.omim.org/entry/608292"},{"mim_id":"176705","title":"PROHIBITIN; PHB","url":"https://www.omim.org/entry/176705"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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PTR","url":"https://pubmed.ncbi.nlm.nih.gov/35599350","citation_count":18,"is_preprint":false},{"pmid":"34781982","id":"PMC_34781982","title":"STOML2 interacts with PHB through activating MAPK signaling pathway to promote colorectal Cancer proliferation.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34781982","citation_count":18,"is_preprint":false},{"pmid":"29415747","id":"PMC_29415747","title":"Flavagline analog FL3 induces cell cycle arrest in urothelial carcinoma cell of the bladder by inhibiting the Akt/PHB interaction to activate the GADD45α pathway.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29415747","citation_count":18,"is_preprint":false},{"pmid":"15170237","id":"PMC_15170237","title":"Roles of poly(3-hydroxybutyrate) depolymerase and 3HB-oligomer hydrolase in bacterial PHB metabolism.","date":"2004","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15170237","citation_count":18,"is_preprint":false},{"pmid":"32221047","id":"PMC_32221047","title":"HDAC6 promotes sepsis development by impairing PHB1-mediated mitochondrial respiratory chain function.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32221047","citation_count":17,"is_preprint":false},{"pmid":"36870657","id":"PMC_36870657","title":"Polyhydroxybutyrate (PHB) in nanoparticulate form improves physical and biological performance of scaffolds.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36870657","citation_count":17,"is_preprint":false},{"pmid":"20946606","id":"PMC_20946606","title":"Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function.","date":"2010","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/20946606","citation_count":17,"is_preprint":false},{"pmid":"24596097","id":"PMC_24596097","title":"A disease-causing mutation illuminates the protein membrane topology of the kidney-expressed prohibitin homology (PHB) domain protein podocin.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24596097","citation_count":17,"is_preprint":false},{"pmid":"35421107","id":"PMC_35421107","title":"Isolation and optimization of extracellular PHB depolymerase producer Aeromonas caviae Kuk1-(34) for sustainable solid waste management of biodegradable polymers.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35421107","citation_count":17,"is_preprint":false},{"pmid":"34154737","id":"PMC_34154737","title":"Preparation and characterisation of organic UV filters based on combined PHB/liposomes with natural phenolic compounds.","date":"2020","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34154737","citation_count":16,"is_preprint":false},{"pmid":"32095890","id":"PMC_32095890","title":"Biocompatible PHB Production from Bacillus Species Under Submerged and Solid-State Fermentation and Extraction Through Different Downstream Processing.","date":"2020","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32095890","citation_count":16,"is_preprint":false},{"pmid":"36257733","id":"PMC_36257733","title":"Novel approach based on GQD-PHB as anchoring platform for the development of SARS-CoV-2 electrochemical immunosensor.","date":"2022","source":"Analytica chimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/36257733","citation_count":16,"is_preprint":false},{"pmid":"25281380","id":"PMC_25281380","title":"Impact of Ralstonia eutropha's poly(3-Hydroxybutyrate) (PHB) Depolymerases and Phasins on PHB storage in recombinant Escherichia coli.","date":"2014","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25281380","citation_count":16,"is_preprint":false},{"pmid":"26496733","id":"PMC_26496733","title":"Prohibitin( PHB) roles in granulosa cell physiology.","date":"2016","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/26496733","citation_count":15,"is_preprint":false},{"pmid":"36235929","id":"PMC_36235929","title":"Polyhydroxybutyrate (PHB)-Based Biodegradable Polymer from Agromyces indicus: Enhanced Production, Characterization, and Optimization.","date":"2022","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/36235929","citation_count":15,"is_preprint":false},{"pmid":"35729556","id":"PMC_35729556","title":"PHB production from cellobiose with Saccharomyces cerevisiae.","date":"2022","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/35729556","citation_count":14,"is_preprint":false},{"pmid":"37532195","id":"PMC_37532195","title":"Osteogenic potential of PHB-lignin/cellulose nanofiber electrospun scaffold as a novel bone regeneration construct.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37532195","citation_count":14,"is_preprint":false},{"pmid":"38964378","id":"PMC_38964378","title":"Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38964378","citation_count":13,"is_preprint":false},{"pmid":"34012957","id":"PMC_34012957","title":"Polyhydroxybutyrate (PHB) Production Using an Arabinose-Inducible Expression System in Comparison With Cold Shock Inducible Expression System in Escherichia coli.","date":"2021","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34012957","citation_count":13,"is_preprint":false},{"pmid":"21999748","id":"PMC_21999748","title":"Identification and characterization of PhbF: a DNA binding protein with regulatory role in the PHB metabolism of Herbaspirillum seropedicae SmR1.","date":"2011","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21999748","citation_count":13,"is_preprint":false},{"pmid":"37623657","id":"PMC_37623657","title":"Evaluation of Biocompatibility of PLA/PHB/TPS Polymer Scaffolds with Different Additives of ATBC and OLA Plasticizers.","date":"2023","source":"Journal of functional biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/37623657","citation_count":13,"is_preprint":false},{"pmid":"27242754","id":"PMC_27242754","title":"Backup Expression of the PhaP2 Phasin Compensates for phaP1 Deletion in Herbaspirillum seropedicae, Maintaining Fitness and PHB Accumulation.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27242754","citation_count":13,"is_preprint":false},{"pmid":"27557820","id":"PMC_27557820","title":"PHB in Cardiovascular and Other Diseases: Present Knowledge and Implications.","date":"2017","source":"Current drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/27557820","citation_count":12,"is_preprint":false},{"pmid":"32859869","id":"PMC_32859869","title":"Prohibitin (PHB) interacts with AKT in mitochondria to coordinately modulate sperm motility.","date":"2020","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/32859869","citation_count":12,"is_preprint":false},{"pmid":"34771358","id":"PMC_34771358","title":"Biosynthesis of Poly-ß-Hydroxybutyrate (PHB) from Different Bacterial Strains Grown on Alternative Cheap Carbon Sources.","date":"2021","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/34771358","citation_count":12,"is_preprint":false},{"pmid":"19699761","id":"PMC_19699761","title":"Construction of PHB and PHBV multiple-gene vectors driven by an oil palm leaf-specific promoter.","date":"2009","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/19699761","citation_count":11,"is_preprint":false},{"pmid":"36364191","id":"PMC_36364191","title":"Characterization of Polyhydroxybutyrate, PHB, Synthesized by Newly Isolated Haloarchaea Halolamina spp.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36364191","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53230,"output_tokens":6067,"usd":0.125348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14508,"output_tokens":4747,"usd":0.095607,"stage2_stop_reason":"end_turn"},"total_usd":0.220955,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian PHB1 (prohibitin 1, also known as PHB or BAP32) gene, versus papers about poly(hydroxybutyrate) biopolymer (also abbreviated PHB) or other unrelated genes. The vast majority of papers (1-2, 5, 7-13, 15-16, 18-22, 24, 27-29, 33-35, 37-40, 42-48, 50-52, 54-55, 57 partial, 60, 62-65, 67-69, 71 partial, 73, 77, 79, 82-84, 85-86, 88-90, 92-95, 97-100) are about the bacterial biopolymer PHB. I will focus on papers clearly about the human/mammalian prohibitin 1 protein.\n\nRelevant papers: 3, 6, 14, 17, 23, 25, 26, 30, 31, 36, 49, 53, 57, 58, 59, 66, 70, 71, 74, 75, 76, 78, 80, 87, 91, 96, 97\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"PHB1 (Phb1p) and PHB2 (Phb2p) localize to the mitochondrial inner membrane where they form a large multimeric ring complex (~12-14 copies of each subunit) that acts as a membrane-bound chaperone, directly binding newly synthesized mitochondrial translation products and stabilizing them against degradation by membrane-bound AAA metalloproteases.\",\n      \"method\": \"Biochemical fractionation, native molecular weight analysis, direct binding assays with mitochondrial translation products\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated findings from multiple labs reviewed here; direct binding and fractionation experiments establishing inner membrane localization and chaperone function for respiratory complex subunit assembly\",\n      \"pmids\": [\"11852914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In human T cells, PHB1 and PHB2 localize to the mitochondrial inner membrane (not the nucleus); PHB1 is serine-phosphorylated and PHB2 is serine- and tyrosine-phosphorylated (Tyr248 mapped by MS and confirmed by mutagenesis). siRNA-mediated knockdown of PHBs disrupts mitochondrial membrane potential, establishing a role for the PHB1/PHB2 phosphocomplex in mitochondrial homeostasis and T cell survival.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, electron microscopy, orthophosphate labeling, phosphoamino acid analysis, mass spectrometry, site-directed mutagenesis, phosphospecific antibodies, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, EM, MS, mutagenesis, siRNA) in single rigorous study establishing localization, phosphorylation sites, and functional consequence\",\n      \"pmids\": [\"18086671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In human ESCs, PHB forms a protein complex with HIRA (a histone H3.3 chaperone), stabilizes HIRA complex components, and together with HIRA controls global deposition of histone H3.3 and gene expression. PHB and HIRA regulate chromatin architecture at isocitrate dehydrogenase gene promoters to promote transcription and α-ketoglutarate production. Genome-wide siRNA screening identified PHB as essential for hESC self-renewal.\",\n      \"method\": \"Genome-wide siRNA screen, co-immunoprecipitation, chromatin assays, gene expression analysis, metabolite measurement\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen identification plus reciprocal co-IP, chromatin, and metabolic readouts in single study establishing nuclear PHB-HIRA complex function\",\n      \"pmids\": [\"27939217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PHB complex deficiency impairs the formation of mitochondrial respiratory supercomplexes (RSCs) without altering the abundance of individual respiratory complex subunits, leading to elevated basal mitochondrial ROS production and increased mitoflash frequency. Co-expression of PHB1 and PHB2 rescues these defects, indicating the multimeric PHB complex is the functional unit for RSC assembly.\",\n      \"method\": \"siRNA knockdown, live-cell mitoflash imaging, ROS measurement, blue native PAGE for RSC analysis, rescue by co-expression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined molecular phenotype (RSC loss), rescue experiment, and multiple orthogonal readouts in single study\",\n      \"pmids\": [\"28630166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM21 acts as an E3 ubiquitin ligase that ubiquitinates PHB1, targeting it for degradation. LPLUNC1 stabilizes PHB1 by competitively impeding the PHB1-TRIM21 interaction (due to stronger binding affinity of LPLUNC1 to PHB1), thus inhibiting PHB1 ubiquitination. PHB1 suppresses NF-κB activity in nasopharyngeal carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, competitive binding assays, PHB1 knockdown/overexpression, NF-κB reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assays establish TRIM21 as E3 ligase for PHB1; competitive binding mechanism supported; single lab\",\n      \"pmids\": [\"30886235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHB overexpression in undifferentiated rat granulosa cells inhibits apoptosis by increasing anti-apoptotic proteins Bcl-2 and Bcl-xL, reducing cytochrome c release from mitochondria, and inhibiting caspase-3 activity via a PHB→MEK-ERK1/2→Bcl-2/Bcl-xL pathway. PHB silencing fragmented mitochondrial morphology and sensitized cells to apoptosis.\",\n      \"method\": \"Microarray, immunoblot, adenoviral overexpression and siRNA knockdown, mitochondrial morphology imaging, caspase activity assay, cytochrome c release measurement\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple downstream readouts; pathway placement via Bcl-2 family and ERK; single lab\",\n      \"pmids\": [\"24096434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PHB overexpression in rat granulosa cells increases mitochondrial PHB content and delays ceramide-induced apoptosis, while adenoviral shRNA silencing of PHB sensitizes cells to ceramide-induced apoptosis. Exogenous ceramide augments mitochondrial PHB expression and causes cytochrome c release and caspase-3 activation, establishing mitochondrial PHB as a critical survival factor in granulosa cells.\",\n      \"method\": \"Adenoviral overexpression and shRNA knockdown, ceramide treatment, cytochrome c release assay, caspase-3 activation measurement\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with defined apoptotic readouts; single lab; supports prior findings\",\n      \"pmids\": [\"21763324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FoxM1 binds the PHB1 promoter and enhances PHB1 expression at transcriptional and post-transcriptional levels. PHB1 interacts with C-RAF and promotes ERK1/2 phosphorylation, contributing to paclitaxel resistance. Knockdown of PHB1 sensitizes pancreatic cancer cells to paclitaxel, and FoxM1 inhibition decreases PHB1, p-ERK1/2, and ABCA2 expression.\",\n      \"method\": \"Promoter binding assay (bioinformatics + reporter), co-immunoprecipitation (PHB1/C-RAF), gene knockdown, phospho-ERK Western blot, in vitro and in vivo paclitaxel resistance assays\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishes PHB1/C-RAF interaction; promoter binding and functional resistance assays; single lab\",\n      \"pmids\": [\"31334335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHB in spermatocytes regulates expression of STAG3 (a meiotic cohesin complex component) via a non-canonical JAK2/STAT pathway. The PHB/JAK2 axis modulates histone H3 tyrosine 41 phosphorylation (H3Y41ph) and H3K9me3 at the Stag3 locus. Loss of PHB in male germ cells (Phb-cKO) causes meiotic pachytene arrest, impaired DSB repair, and complete male infertility, also associated with mitochondrial dysfunction.\",\n      \"method\": \"Conditional knockout mouse (Phb-cKO), meiotic staging, immunofluorescence, ChIP (H3Y41ph, H3K9me3 at Stag3 locus), Western blot for JAK2/STAT pathway components, STAG3 expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with defined meiotic phenotype, ChIP-based epigenetic mechanism, and pathway placement via JAK2 axis; multiple orthogonal methods\",\n      \"pmids\": [\"32232334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHCHD10 interacts with SLP2 (Stomatin-Like Protein 2) and participates in stabilizing the prohibitin complex in the mitochondrial inner membrane. The ALS/FTD-linked CHCHD10(S59L) variant causes SLP2-prohibitin aggregates and instability of the PHB complex, leading to OMA1 cascade activation, OPA1 processing, mitochondrial fragmentation, abnormal cristae morphogenesis, and motor neuron death. PHB complex destabilization disrupts the mitochondrial contact site and cristae organizing system (MICOS) complex, likely via disruption of OPA1-mitofilin interaction.\",\n      \"method\": \"Patient fibroblasts, mouse model (Chchd10S59L/+), co-immunoprecipitation, immunofluorescence, spinal cord histology, mitochondrial morphology analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient fibroblasts and mouse model with reciprocal co-IP and defined in vivo pathological phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"35656794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FL3 (a flavagline) inhibits the interaction between Akt and PHB1 and inhibits Akt-mediated PHB1 phosphorylation, which decreases PHB1 localization to mitochondria. This activates the GADD45α pathway leading to G2/M cell cycle arrest in bladder carcinoma cells. Knockdown of PHB1 mimics FL3-induced cell cycle inhibition, and knockdown of GADD45α rescues the inhibitory effect of FL3.\",\n      \"method\": \"Co-immunoprecipitation (Akt-PHB interaction), phosphorylation assays, subcellular fractionation, mRNA microarray, PHB1 knockdown, GADD45α knockdown, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishes Akt-PHB interaction; fractionation shows localization change; epistasis via GADD45α knockdown; single lab\",\n      \"pmids\": [\"29415747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOML2 interacts with PHB (PHB1) as demonstrated by yeast two-hybrid screening and confirmed by co-immunoprecipitation and co-localization in cell lines and tissues. Both STOML2 and PHB activate the MAPK signaling pathway (RAF1-MEK1/2-ERK1/2 phosphorylation) to promote colorectal cancer proliferation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization, STOML2 knockdown, MAPK pathway Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP confirms interaction; pathway activation by Western blot; single lab\",\n      \"pmids\": [\"34781982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHB1 knockdown increases cytoplasmic mtDNA levels and enhances NLRP3 inflammasome activation. Mitophagy inhibitor treatment abolishes PHB1 knockdown-mediated NLRP3 activation, establishing that PHB1 inhibits NLRP3 inflammasome activation through promoting mitophagy.\",\n      \"method\": \"PHB1 siRNA knockdown, mtDNA cytoplasmic measurement, NLRP3 inflammasome activation assays, mitophagy inhibitor treatment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype and pharmacological epistasis establishing mitophagy-dependent mechanism; single lab\",\n      \"pmids\": [\"37359543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHB interacts with AKT in the mitochondrial sheath of sperm, forming a complex with phospho-PHB (pT258) and phospho-AKT. Blocking PI3K/AKT activity with wortmannin decreases PHB phosphorylation at T258 and reduces sperm motility. Infertile asthenospermic men show reduced phospho-PI3K, phospho-AKT, and phospho-PHB (pT258) levels, suggesting AKT-mediated PHB phosphorylation at T258 regulates sperm motility.\",\n      \"method\": \"Co-localization microscopy, co-immunoprecipitation, pharmacological inhibition (wortmannin), phosphospecific antibodies, human sperm analysis\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishes PHB-AKT interaction in mitochondria; pharmacological epistasis links AKT to PHB phosphorylation and motility; single lab\",\n      \"pmids\": [\"32859869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC6 downregulates PHB1 expression and function, impairing PHB1-mediated mitochondrial respiratory chain function, increasing oxidant production and oxidative stress, thereby promoting sepsis development. Inhibition of HDAC6 attenuates CLP-induced sepsis through restoration of mitochondrial function.\",\n      \"method\": \"CLP rat sepsis model, HDAC6 inhibition, RT-PCR, Western blot, mitochondrial respiratory control rate measurement\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Western blot and functional respiratory rate measurement; mechanism of HDAC6 regulation of PHB1 not directly demonstrated at molecular level\",\n      \"pmids\": [\"32221047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Arctigenin elevates PHB1 protein levels by blocking TRIM21-mediated ubiquitination of PHB1 via estrogen receptor β (ERβ)-dependent competitive interaction: ERβ activation allows it to competitively bind PHB1 and disrupt the TRIM21-PHB1 interaction, preventing PHB1 ubiquitination-mediated degradation and inhibiting mitochondrial apoptosis in goblet cells.\",\n      \"method\": \"In vitro and in vivo colitis models, ERβ knockdown in mice, co-immunoprecipitation (ERβ-PHB1, TRIM21-PHB1), ubiquitination assays, Western blot\",\n      \"journal\": \"Phytotherapy research : PTR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assays establish competitive binding mechanism; in vivo ERβ knockdown epistasis; single lab; corroborates TRIM21-PHB1 interaction from prior work\",\n      \"pmids\": [\"35599350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHB1 (prohibitin) binds to β-catenin and stabilizes it by inhibiting ubiquitin-mediated degradation, thereby increasing Wnt/β-catenin signaling activity and promoting bladder cancer cell EMT, migration, invasion, and metastasis. β-catenin knockdown reduces cancer cell migration and invasion in PHB1-overexpressing cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, gene knockdown/overexpression, transwell/wound-healing assays, in vivo lung metastasis nude mouse model, Western blot\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishes PHB1-β-catenin interaction; epistasis via β-catenin KD; in vivo validation; single lab\",\n      \"pmids\": [\"37235908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHB1 interacts with Sam50 (a mitochondrial outer membrane protein) and together they stabilize mtDNA. Lycopene protects against atrazine-induced kidney damage by interacting with Sam50/PHB1 to prevent mtDNA instability, cytoplasmic mtDNA release, and downstream cGAS-STING pathway activation leading to PANoptosis.\",\n      \"method\": \"In vivo mouse model (atrazine + lycopene), Sam50/PHB1 interaction assays, mtDNA stability measurement, mPTP and BAX pore assays, cGAS-STING pathway analysis\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction assays described but abstract lacks detail on direct binding method; single lab; mechanistic chain proposed with limited molecular resolution in abstract\",\n      \"pmids\": [\"38820047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Saccharomyces cerevisiae, both Phb1 and Phb2 (orthologs of human PHB1/PHB2) function as Atg8 receptors to support mitophagy via conserved AIM/LIR-like motifs. Phb1 and Phb2 interact with and co-localize with Atg8 at mitochondria. The prohibitin complex also negatively regulates Atg32 processing: in the absence of prohibitins, Atg32 C-terminal processing is enhanced in a manner dependent on the rhomboid protease Pcp1 (and the i-AAA protease Yme1).\",\n      \"method\": \"Yeast Phb1/Phb2 deletion mutants, mitophagy assays, co-immunoprecipitation (Phb1/Phb2 with Atg8), AIM/LIR motif mutagenesis, Atg32 processing assays, genetic epistasis (Yme1, Pcp1 deletion)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, mutagenesis of AIM/LIR motif, genetic epistasis) establishing novel receptor function for mitophagy in yeast orthologs; consistent with mammalian PHB2 mitophagy role\",\n      \"pmids\": [\"38964378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHBs (PHB1 and PHB2) are directly associated with the eukaryotic initiation factor 4F (eIF4F) translation complex in CLL cells, as shown by multiomics and knockdown experiments. PHB knockdown mimics treatment with the PHB-binding drug FL3, inhibiting MYC oncogene translation and reducing translation of cell cycle and metabolic proteins. The RAS-RAF-(PHB)-MAPK pathway is not implicated in translation regulation in CLL (negative finding in this context).\",\n      \"method\": \"Multiomics (proteomics/transcriptomics), PHB knockdown, FL3 pharmacological inhibition, ribosome profiling/translation assays, in vivo CLL mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiomics plus knockdown phenocopy of drug; direct PHB-eIF4F association established; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37084385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHB1 (prohibitin 1) is a mitochondrial inner membrane scaffold protein that, together with PHB2, forms a large multimeric ring complex acting as a membrane-bound chaperone for respiratory complex assembly, stabilizes respiratory supercomplexes, maintains mitochondrial membrane potential and cristae integrity, and undergoes AKT-mediated phosphorylation; it also functions in the nucleus (complexed with HIRA to regulate histone H3.3 deposition and metabolic gene expression), undergoes TRIM21-mediated ubiquitination (counteracted by LPLUNC1 or ERβ), interacts with C-RAF/ERK and β-catenin signaling, acts as an Atg8/LC3-interacting receptor for mitophagy via AIM/LIR motifs, and directly associates with the eIF4F translation initiation complex to regulate oncogene translation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHB1 (prohibitin 1) is a multifunctional scaffold protein best characterized as a mitochondrial inner-membrane chaperone that, with PHB2, assembles into a large multimeric ring complex (~12–14 copies of each subunit) which binds newly synthesized mitochondrial translation products and protects them from membrane-bound AAA proteases [#0]. Through this scaffold the PHB complex stabilizes respiratory supercomplex assembly without changing individual complex subunit abundance, limiting basal ROS production and preserving mitochondrial membrane potential [#1, #3]. The complex is itself stabilized in the inner membrane through associations with SLP2/STOML2 and CHCHD10, and its destabilization disrupts cristae organization (MICOS) and triggers the OMA1–OPA1 fragmentation cascade [#9, #11]. Beyond bioenergetics, PHB1 supports mitochondrial quality control: in yeast orthologs the prohibitin subunits act as Atg8/LC3 receptors driving mitophagy via AIM/LIR motifs and restrain Atg32 processing [#18], and in mammalian cells PHB1 promotes mitophagy to clear damaged mtDNA and thereby limit NLRP3 inflammasome activation [#12]. PHB1 also operates outside mitochondria, forming a nuclear complex with the histone H3.3 chaperone HIRA to control H3.3 deposition, isocitrate dehydrogenase gene transcription, and α-ketoglutarate production required for ESC self-renewal [#2], and regulating meiotic STAG3 expression through a JAK2/STAT-dependent histone modification pathway essential for male fertility [#8]. PHB1 abundance is set by TRIM21-mediated ubiquitination and degradation, which is competitively blocked by LPLUNC1 or ERβ [#4, #15], and its activity is modulated by AKT-mediated phosphorylation that controls its mitochondrial localization [#10, #13]. In cancer contexts PHB1 scaffolds C-RAF/STOML2-driven ERK/MAPK signaling, stabilizes β-catenin to drive Wnt signaling and EMT, and associates with the eIF4F initiation complex to promote oncogene (MYC) translation [#7, #11, #16, #19].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the founding molecular function of PHB1: that it and PHB2 form a ring-shaped membrane-bound chaperone protecting nascent mitochondrial translation products from proteolysis.\",\n      \"evidence\": \"Biochemical fractionation, native molecular weight analysis, and direct binding to mitochondrial translation products\",\n      \"pmids\": [\"11852914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ring assembly not resolved\", \"Did not address non-mitochondrial functions\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved where PHB1 acts in human cells and that it is post-translationally modified, linking the phosphorylated PHB1/PHB2 complex to membrane potential and cell survival.\",\n      \"evidence\": \"Subcellular fractionation, EM, MS phosphosite mapping, mutagenesis, and siRNA knockdown in human T cells\",\n      \"pmids\": [\"18086671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for PHB1 serine phosphorylation not identified\", \"Functional role of specific PHB1 phosphosites unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a distinct nuclear function for PHB1 as a HIRA partner coupling histone H3.3 deposition to metabolic gene expression and stem cell self-renewal.\",\n      \"evidence\": \"Genome-wide siRNA screen, reciprocal co-IP, chromatin assays, and metabolite measurement in human ESCs\",\n      \"pmids\": [\"27939217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PHB1 partitions between mitochondria and nucleus unknown\", \"Direct DNA/chromatin contact by PHB1 not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the functional consequence of PHB chaperone activity is respiratory supercomplex assembly, distinguishing assembly from subunit abundance.\",\n      \"evidence\": \"siRNA knockdown, blue native PAGE, mitoflash imaging, ROS measurement, and co-expression rescue\",\n      \"pmids\": [\"28630166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contacts between PHB ring and supercomplex subunits not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that PHB1 controls meiotic progression in vivo by regulating cohesin (STAG3) through a non-canonical JAK2/STAT–histone modification axis.\",\n      \"evidence\": \"Conditional knockout mouse, meiotic staging, ChIP for H3Y41ph/H3K9me3 at the Stag3 locus, pathway Western blots\",\n      \"pmids\": [\"32232334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PHB1 directly engages JAK2 vs. acts indirectly unclear\", \"Relative contribution of mitochondrial vs. epigenetic roles to infertility not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed the PHB complex within the inner-membrane organizing network, showing its stability depends on SLP2/CHCHD10 and its loss collapses cristae via OMA1–OPA1 and MICOS disruption.\",\n      \"evidence\": \"Patient fibroblasts and CHCHD10(S59L) mouse model with reciprocal co-IP and morphology analysis\",\n      \"pmids\": [\"35656794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PHB1–OPA1/mitofilin contacts inferred rather than proven\", \"Stoichiometry of SLP2–PHB assembly not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified prohibitins as direct Atg8/LC3 mitophagy receptors via AIM/LIR motifs and as negative regulators of Atg32 processing, defining a quality-control function.\",\n      \"evidence\": \"Yeast deletion mutants, co-IP with Atg8, AIM/LIR mutagenesis, and genetic epistasis with Yme1/Pcp1\",\n      \"pmids\": [\"38964378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated in yeast orthologs; mammalian PHB1 LIR-dependent receptor role not directly tested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked PHB1-driven mitophagy to innate immune control by showing it limits cytoplasmic mtDNA accumulation and NLRP3 inflammasome activation.\",\n      \"evidence\": \"siRNA knockdown, cytoplasmic mtDNA quantification, NLRP3 activation assays, and mitophagy inhibitor epistasis\",\n      \"pmids\": [\"37359543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single loss-of-function study\", \"Whether PHB1 acts as the receptor in this mammalian mitophagy not shown directly\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established TRIM21 as the E3 ligase setting PHB1 abundance and LPLUNC1 as a competitive stabilizer, defining how PHB1 levels are controlled.\",\n      \"evidence\": \"Co-IP, ubiquitination and competitive binding assays, knockdown/overexpression, and NF-κB reporters in nasopharyngeal carcinoma\",\n      \"pmids\": [\"30886235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIM21 ubiquitination site on PHB1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the TRIM21 degradation axis by showing ERβ competitively protects PHB1, corroborating the regulated-degradation model in a second disease context.\",\n      \"evidence\": \"Colitis models, ERβ knockdown in mice, co-IP and ubiquitination assays\",\n      \"pmids\": [\"35599350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERβ–PHB1 binding interface not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed AKT-mediated phosphorylation governs PHB1 mitochondrial localization and downstream proliferation control via GADD45α.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, fractionation, microarray, and GADD45α knockdown epistasis in bladder carcinoma\",\n      \"pmids\": [\"29415747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AKT phosphosite on PHB1 not mapped in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped a specific AKT phosphosite (T258) on PHB1 in sperm and connected PI3K/AKT–PHB1 signaling to motility and human asthenospermia.\",\n      \"evidence\": \"Co-localization, co-IP, wortmannin inhibition, phosphospecific antibodies, and human sperm analysis\",\n      \"pmids\": [\"32859869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional readout correlative in human samples\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified STOML2 as a direct PHB1 partner that co-activates RAF1–MEK–ERK signaling to promote proliferation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, co-localization, knockdown, and MAPK Western blots in colorectal cancer\",\n      \"pmids\": [\"34781982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STOML2–PHB1 acts via mitochondrial or cytosolic pool unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined two additional pro-oncogenic mechanisms: PHB1 stabilization of β-catenin driving Wnt/EMT, and direct PHB association with eIF4F to promote MYC translation.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, migration/metastasis assays (β-catenin); multiomics, knockdown, and FL3 phenocopy with ribosome profiling (eIF4F)\",\n      \"pmids\": [\"37235908\", \"37084385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. scaffold-mediated PHB1–eIF4F binding not fully resolved\", \"RAS-RAF-MAPK explicitly not implicated in CLL translation control\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHB1 is partitioned among mitochondrial, nuclear, cytosolic and translational pools, and how a single ring chaperone is repurposed for chromatin, signaling and translation roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking the inner-membrane ring to extra-mitochondrial functions\", \"Trafficking/targeting signals directing PHB1 to nucleus or eIF4F not identified\", \"Phosphorylation/ubiquitination code coordinating the multiple pools not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1428517\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"PHB1/PHB2 ring complex\",\n      \"PHB-HIRA complex\",\n      \"SLP2-prohibitin complex\",\n      \"eIF4F complex\"\n    ],\n    \"partners\": [\n      \"PHB2\",\n      \"HIRA\",\n      \"TRIM21\",\n      \"STOML2\",\n      \"CHCHD10\",\n      \"CRAF\",\n      \"AKT\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}