{"gene":"FBXO32","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2001,"finding":"Atrogin-1/FBXO32 contains a functional F-box domain that binds Skp1, and thereby associates with Roc1 and Cul1 to form an SCF-type E3 ubiquitin ligase complex; it also contains a nuclear localization sequence and PDZ-binding domain.","method":"Molecular cloning, domain identification, co-immunoprecipitation with SCF complex components (Skp1, Roc1, Cul1)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding partners identified by Co-IP and functional domain confirmed; foundational paper replicated extensively","pmids":["11717410"],"is_preprint":false},{"year":2004,"finding":"Foxo3 transcription factor acts on the atrogin-1 promoter to drive its transcription; PI3K/AKT pathway activation inhibits Foxo factors and thereby suppresses atrogin-1 expression. Dominant-negative Foxo or RNAi knockdown of Foxo in vivo prevents starvation-induced atrogin-1 induction and muscle atrophy.","method":"Promoter reporter assay, constitutively active Foxo3 overexpression, dominant-negative Foxo construct, RNAi in mouse muscles in vivo, IGF-1/AKT overexpression","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (promoter assay, gain-of-function, loss-of-function in cells and in vivo), widely replicated","pmids":["15109499"],"is_preprint":false},{"year":2004,"finding":"The purified recombinant SCF(MAFbx) complex ubiquitinates MyoD in vitro in a lysine-dependent manner; mutation of lysine 133 in MyoD prevents its ubiquitination by SCF(MAFbx). MAFbx binds MyoD through an LXXLL motif in MyoD and an inverted LXXLL motif in MAFbx. Overexpression of MAFbx suppresses MyoD-induced differentiation and myotube formation.","method":"In vitro ubiquitination reconstitution with purified recombinant SCF(MAFbx), site-directed mutagenesis of MyoD K133, co-immunoprecipitation, overexpression in myoblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis confirming specific ubiquitination site; mechanistic detail confirmed by multiple orthogonal methods in one study","pmids":["15531760"],"is_preprint":false},{"year":2004,"finding":"IGF-1 suppresses atrogin-1 expression by blocking mRNA synthesis (not by affecting mRNA degradation) through the PI3K/Akt pathway. Inhibition of PI3K-Akt (but not calcineurin-NFAT or MEK-ERK) increased atrogin-1 mRNA and proteolysis.","method":"mRNA stability assay, PI3K/Akt pathway inhibition, pathway-specific inhibitors, myotube culture","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pathway inhibitors used to dissect transcriptional mechanism, replicated across labs","pmids":["15100091"],"is_preprint":false},{"year":2005,"finding":"TNF-α induces atrogin-1/MAFbx expression in skeletal muscle via p38 MAPK signaling; p38 inhibitors (SB203580, curcumin) blunt the TNF-α-induced increase in atrogin-1 mRNA and ubiquitin conjugating activity, whereas ERK and JNK inhibitors do not.","method":"Pharmacological inhibitors of p38, ERK, JNK in C2C12 myotubes; in vivo TNF-α injection in mice; ubiquitin conjugating activity assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — dissection of specific MAPK pathway using multiple inhibitors in vitro and in vivo, replicated across models","pmids":["15746179"],"is_preprint":false},{"year":2008,"finding":"eIF3-f (eukaryotic initiation factor 3 subunit 5) is a direct substrate of MAFbx/Atrogin-1; MAFbx polyubiquitinates eIF3-f targeting it for proteasomal degradation. Blockade of MAFbx by shRNA prevents eIF3-f degradation during atrophy, and genetic activation of eIF3-f is sufficient to cause hypertrophy and block atrophy in myotubes.","method":"Ectopic MAFbx overexpression in myotubes, shRNA knockdown, co-immunoprecipitation, proteasome inhibitor rescue, in vivo hypertrophy assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (overexpression, RNAi, rescue experiments) in cells and in vivo, well-replicated substrate identification","pmids":["18354498"],"is_preprint":false},{"year":2008,"finding":"MAFbx/Atrogin-1 polyubiquitinates eIF3-f at multiple C-terminal lysine residues (six lysines in the conserved C-terminal domain are required for full polyubiquitination and degradation). Mutation of all six lysines (K5-10R mutant) produces a hypertrophic gain-of-function in cells and in vivo and protects against starvation-induced atrophy.","method":"Deletion analysis, site-directed mutagenesis of eIF3-f lysines, in vitro ubiquitination, in vivo overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination with mutagenesis identifying specific ubiquitination sites, validated in vivo, single lab","pmids":["19073596"],"is_preprint":false},{"year":2008,"finding":"Atrogin-1/MAFbx interacts with and ubiquitinates MAPK phosphatase-1 (MKP-1), targeting it for proteasomal degradation. Loss of MKP-1 leads to sustained JNK activation and enhanced cardiomyocyte apoptosis following simulated ischemia/reperfusion.","method":"Co-immunoprecipitation, proteasome inhibitor rescue of MKP-1 degradation, JNK inhibitor (SP600125) rescue assay, overexpression in cardiomyocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP confirmed interaction and proteasome inhibitor confirmed degradation pathway, but single lab with no in vitro reconstitution","pmids":["19117950"],"is_preprint":false},{"year":2009,"finding":"MAFbx targets MyoD for degradation in multiple skeletal muscle atrophy models; MAFbx undergoes cytoplasmic-nuclear shuttling during atrophy and selectively suppresses MyoD. shRNA-mediated MAFbx silencing inhibits MyoD proteolysis. Overexpression of a ubiquitination-deficient MyoD mutant (K133R) prevents atrophy of mouse primary myotubes and skeletal muscle fibers in vivo.","method":"shRNA knockdown of MAFbx in myotubes, subcellular fractionation/localization, overexpression of MyoDK133R mutant in vivo, protein degradation assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo rescue with ubiquitination-deficient mutant, multiple atrophy models, RNAi validation; replicates prior in vitro ubiquitination finding","pmids":["19319192"],"is_preprint":false},{"year":2009,"finding":"MAFbx/Atrogin-1 is identified as the F-box protein responsible for polyubiquitination of myogenin in atrophying myotubes; MAFbx overexpression causes MG132-sensitive (proteasome-dependent) reduction of myogenin. Myogenin contains a MAFbx-recognition motif and physically interacts with MAFbx.","method":"Co-immunoprecipitation, overexpression with proteasome inhibitor rescue, myogenin ubiquitination assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and proteasome inhibitor rescue, single lab, no full in vitro reconstitution","pmids":["19631210"],"is_preprint":false},{"year":2009,"finding":"Atrogin-1 co-immunoprecipitates with truncated (M7t) but not wild-type cardiac myosin-binding protein C (cMyBP-C); overexpression of atrogin-1 decreases M7t-cMyBP-C protein level by ~80% in a proteasome-dependent manner, while leaving wild-type cMyBP-C unaffected.","method":"Adenoviral overexpression in cardiac myocytes, co-immunoprecipitation, proteasome inhibitor rescue","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and proteasome inhibitor rescue in primary cardiomyocytes, single lab","pmids":["19850579"],"is_preprint":false},{"year":2007,"finding":"Atrogin-1/MAFbx mediates statin-induced muscle damage; lovastatin induces atrogin-1 expression in humans, zebrafish, and mouse myotubes. atrogin-1 null cells are largely spared from lovastatin-induced morphological changes; atrogin-1 knockdown in zebrafish prevents lovastatin-induced muscle fiber damage. Statin damage is linked to inhibition of geranylgeranylation, not cholesterol synthesis.","method":"Atrogin-1 null cell lines, zebrafish knockdown, lovastatin treatment, geranylgeraniol/farnesol rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null cells, zebrafish knockdown, and pharmacological rescue across three model systems","pmids":["17992259","19406843"],"is_preprint":false},{"year":2011,"finding":"C/EBPβ is activated downstream of p38 MAPK and binds a specific C/EBPβ-responsive cis-element in the atrogin-1/MAFbx gene promoter to drive its transcription during cancer cachexia. p38α/β MAPK inhibitor blocks C/EBPβ binding and atrogin-1 induction; C/EBPβ-knockout mice are resistant to LLC tumor-induced atrogin-1 upregulation and muscle wasting.","method":"Promoter reporter assay, chromatin immunoprecipitation, C/EBPβ knockout mice, p38 MAPK inhibitor, siRNA knockdown in C2C12 myotubes","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, promoter assay, KO mice, and chemical inhibition used; in vivo validation in tumour-bearing mice","pmids":["21847090"],"is_preprint":false},{"year":2012,"finding":"p38β MAPK, but not p38α, specifically phosphorylates C/EBPβ at Thr-188, which is critical for C/EBPβ DNA-binding activity and subsequent binding to the atrogin-1/MAFbx promoter. A C/EBPβ T188A dominant-negative mutant blocks atrogin-1 upregulation; this effect is absent in C/EBPβ-null mice.","method":"Tryptic phosphopeptide mapping, chromatin immunoprecipitation, site-directed mutagenesis of C/EBPβ, siRNA knockdown of p38α/β, in vivo tibialis anterior injection","journal":"Skeletal muscle","confidence":"High","confidence_rationale":"Tier 1 / Moderate — phosphopeptide mapping identifying specific phosphorylation site combined with mutagenesis, ChIP, and in vivo validation; single lab","pmids":["23046544"],"is_preprint":false},{"year":2014,"finding":"Atrogin-1 targets CHMP2B (charged multivesicular body protein 2B, a component of the ESCRT autophagy complex) for ubiquitin-mediated degradation. Loss of atrogin-1 in KO mice causes CHMP2B accumulation, impaired autophagy, intracellular protein aggregate accumulation, UPR activation, cardiomyocyte apoptosis, and progressive cardiomyopathy. CHMP2B downregulation in atrogin-1 KO mice restores autophagy.","method":"Atrogin-1 KO mice, in vivo pulsed SILAC proteomics, co-immunoprecipitation, biochemical fractionation, CHMP2B siRNA rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with proteomics substrate identification, Co-IP confirmation, and rescue experiment; rigorous multi-method study","pmids":["24789905"],"is_preprint":false},{"year":2014,"finding":"MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart; MAFbx/Atrogin-1 KO hearts undergo hypertrophy instead of atrophy following mechanical unloading (heterotopic transplantation). In KO hearts, calcineurin accumulates and NFAT transcriptional activity and protein synthesis rates are increased; calcineurin inhibition normalizes NFAT activity. MAFbx/Atrogin-1 thus suppresses calcineurin-driven hypertrophy during unloading.","method":"MAFbx/Atrogin-1 KO mice, heterotopic heart transplantation model, calcineurin protein measurement, NFAT luciferase reporter, protein synthesis measurement, calcineurin inhibitor rescue","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with mechanistic pathway (calcineurin/NFAT) identified and rescued by inhibitor; validated in human LVAD samples","pmids":["24650875"],"is_preprint":false},{"year":2015,"finding":"FBXO32/Atrogin-1 targets c-Myc for ubiquitination and proteasomal degradation; mutation of lysine 326 in c-Myc reduces ubiquitination and prevents FBXO32-induced degradation. Phosphorylation of c-Myc at Thr-58/Ser-62 is dispensable for FBXO32-mediated degradation. FBXO32 is itself a direct transcriptional target of c-Myc, creating a negative feedback loop.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (c-Myc K326R), luciferase reporter assay, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis identifying ubiquitination site, reporter assay for negative feedback; single lab","pmids":["25944903"],"is_preprint":false},{"year":2016,"finding":"FBXO32 directly ubiquitinates CtBP1, which is required for CtBP1 stability and nuclear retention, enabling epigenetic remodeling and transcriptional induction of CtBP1 target genes that promote epithelial-mesenchymal transition (EMT). FBXO32 knockdown inhibits tumor growth and metastasis in a xenograft model.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear/cytoplasmic fractionation, NSG mouse xenograft, transcriptomic analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay confirmed CtBP1 as substrate; in vivo xenograft confirms functional role; single lab","pmids":["29142217"],"is_preprint":false},{"year":2016,"finding":"A missense mutation in FBXO32 impairs binding to SCF complex proteins (validated by co-immunoprecipitation in cells expressing mutant protein and in patient heart tissue), leading to autophagy impairment and dilated cardiomyopathy. Patient hearts show accumulation of proteins regulating autophagy.","method":"Co-immunoprecipitation from patient heart tissue and transfected cells, whole exome sequencing, protein accumulation assay","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from patient tissue validates functional consequence of mutation; single family with limited replication","pmids":["26753747"],"is_preprint":false},{"year":2016,"finding":"FBXO32/Atrogin-1 interacts with all three endophilin-A proteins; FBXO32 overexpression triggers apoptosis in neurons, but co-expression of endophilin-A rescues this. FBXO32 tubulates membranes and localizes on clathrin-coated structures and transiently co-localizes with autophagosomes. Both FBXO32 and endophilin-A are required for autophagosome formation.","method":"Co-immunoprecipitation, live cell imaging (localization on clathrin-coated structures and autophagosomes), overexpression/rescue experiments, autophagy flux assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interactions, live imaging established localization; rescue experiment demonstrated functional relationship; single lab","pmids":["27720640"],"is_preprint":false},{"year":2017,"finding":"FBXO32 physically interacts with the N-terminus (1–60 aa) of KLF4 via its C-terminus (228–355 aa), and the F-box domain is required for FBXO32-dependent KLF4 ubiquitination and degradation. p38 MAPK pathway activity is implicated in this process, as p38 inhibitor abrogates KLF4 ubiquitination.","method":"Genome-wide E3 ligase siRNA screen, co-immunoprecipitation, domain mapping, ubiquitination assay, p38 inhibitor treatment, in vivo tumor growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen followed by Co-IP and domain mapping; ubiquitination assay confirmed; single lab","pmids":["28068319"],"is_preprint":false},{"year":2008,"finding":"TNF-α increases nuclear Foxo4 protein and atrogin-1 mRNA independently of AKT and Foxo1/Foxo3; siRNA against Foxo4 reduces the TNF-induced increase in atrogin-1 mRNA. TNF does not affect Foxo1/3 nuclear localization despite increasing atrogin-1 expression.","method":"PI3K inhibitor (wortmannin), siRNA against Foxo4, IGF stimulation, subcellular fractionation, qRT-PCR in C2C12 myotubes","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with nuclear localization assay; single lab, limited orthogonal methods","pmids":["18701653"],"is_preprint":false},{"year":2013,"finding":"Smad3 is sufficient to stimulate atrogin-1 promoter activity, inhibit Akt/mTOR signaling and protein synthesis, and induce muscle fiber atrophy in vivo. Smad3-induced inhibition of mTOR is proposed to occur via reduced miR-29 expression and increased PTEN translation.","method":"In vivo plasmid transfection (transient transgenic mouse muscle), promoter reporter assay, protein synthesis measurement, mTOR pathway analysis","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transfection with promoter reporter and functional phenotype; single lab","pmids":["24002653"],"is_preprint":false},{"year":2010,"finding":"FOXO3a mediates crosstalk between PI3K/Akt and MEK/ERK pathways to coordinate atrogin-1 and ubiquitin expression; knockdown of IRS-1 or constitutively active FOXO3a increases IRS-2 protein, MEK/ERK signaling, and ubiquitin expression, linking the two atrogene transcription programs.","method":"siRNA knockdown of IRS-1, adenovirus-mediated constitutively active FOXO3a expression, Western blotting, streptozotocin diabetes rat model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation (siRNA, adenovirus) in cells and in vivo rat model; single lab","pmids":["20371624"],"is_preprint":false},{"year":2015,"finding":"Pak1 activation under pressure overload upregulates Fbxo32 expression through Smad3 binding to an AGAC(-286) site on the FBXO32 promoter. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling in cardiac-specific Pak1 KO mice.","method":"Cardiac-specific Pak1 KO mice, constitutively active Pak1 overexpression, chromatin immunoprecipitation (Smad3 binding to FBXO32 promoter), promoter mutagenesis, berberine treatment","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed specific Smad3 binding site on FBXO32 promoter; KO mouse and pharmacological rescue validate pathway; single lab","pmids":["26483344"],"is_preprint":false},{"year":2021,"finding":"Mutant FBXO32 impairs ATF2 ubiquitination; ATF2 protein physically interacts with FBXO32 in the human heart, and expression of mutant FBXO32 is sufficient to induce CHOP-associated apoptosis. FBXO32 mutation causes up-regulation of CHOP and its target genes through a non-canonical pathway.","method":"Co-immunoprecipitation of ATF2 with FBXO32 from human heart, ubiquitination assay, overexpression of mutant FBXO32 in cells, transcriptional profiling","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from patient heart tissue, ubiquitination assay, functional overexpression; single lab, limited replication","pmids":["34272480"],"is_preprint":false},{"year":2020,"finding":"Atrogin-1-mediated ubiquitination of aquaporin 4 (AQP4) targets it for degradation in atrophying muscle; AQP4 knockdown reduces myotube size. HMGB1 acts upstream of atrogin-1 via NF-κB signaling to increase atrogin-1 expression.","method":"Ubiquitination assay after AQP4 immunoprecipitation, AQP4 knockdown in myotubes, recombinant HMGB1 treatment, NF-κB pathway analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination assay after immunoprecipitation confirmed AQP4 as substrate; single lab, no in vitro reconstitution","pmids":["32843684"],"is_preprint":false},{"year":2022,"finding":"FBXO32 acts as an E3 ubiquitin ligase for PHPT1; knockdown of FBXO32 leads to PHPT1 accumulation and activation of the ERK/MAPK pathway, promoting lung cancer cell proliferation.","method":"Co-immunoprecipitation, mass spectrometry, western blotting, siRNA knockdown of FBXO32, in vitro and in vivo tumor growth assays","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and mass spectrometry identified substrate; knockdown confirmed pathway activation; single lab","pmids":["35411430"],"is_preprint":false},{"year":2021,"finding":"FBXO32 and SMARCA4 (a component of the BAF/PBAF chromatin remodeling complex) physically interact; FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32 (e.g., CDK6), suggesting FBXO32 controls transcription through regulation of chromatin remodeling complex activity. FBXO32 is identified as a MITF target gene.","method":"Co-immunoprecipitation, proteomic analysis, ChIP at FBXO32-regulated loci, transcriptomic analysis after FBXO32 knockdown, in vivo tumor model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed SMARCA4 as partner; ChIP showed co-localization at target loci; single lab","pmids":["33462405"],"is_preprint":false},{"year":2011,"finding":"EZH2 represses FBXO32 transcription via H3K27 trimethylation at the FBXO32 promoter in PAX3-FOXO1 alveolar rhabdomyosarcoma; EZH2 depletion causes transcriptional derepression of FBXO32 and FBXO32-dependent apoptosis. Simultaneous knockdown of FBXO32 and EZH2 impairs the pro-apoptotic response.","method":"EZH2 siRNA knockdown, FBXO32 promoter ChIP for H3K27me3 and EZH2 occupancy, overexpression of FBXO32, pharmacological EZH2 inhibition, in vivo tumor growth","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed epigenetic repression mechanism; genetic and pharmacological rescue validated in vivo; single lab","pmids":["24213577"],"is_preprint":false},{"year":2019,"finding":"Atrogin-1/MAFbx mRNA expression in rat soleus muscle under hindlimb unloading is regulated by HDAC1; pharmacological inhibition of HDAC1 (CI-994) prevents the unloading-induced increase in MAFbx and ubiquitin expression, without affecting MuRF-1 expression.","method":"HDAC1 inhibitor CI-994 treatment in hindlimb-suspended rats, nuclear fractionation of HDAC1, RT-PCR, Western blotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological inhibition with subcellular fractionation; specific to MAFbx but not MuRF1; single lab","pmids":["31311969"],"is_preprint":false}],"current_model":"FBXO32/Atrogin-1/MAFbx is a muscle-enriched F-box protein that assembles into an SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex; it polyubiquitinates multiple substrates—including MyoD (at K133), myogenin, eIF3-f (at C-terminal lysines), MKP-1, CHMP2B, calcineurin, cMyBP-C (truncated mutants), AQP4, KLF4, c-Myc, CtBP1, PHPT1, and ATF2—targeting them for proteasomal degradation, thereby regulating skeletal and cardiac muscle protein homeostasis, autophagy flux, cell growth, and epithelial–mesenchymal transition; its transcription is controlled by FOXO transcription factors downstream of PI3K/Akt, by p38β MAPK-phosphorylated C/EBPβ binding to its promoter, by Smad3 (downstream of Pak1 or TGF-β/myostatin), and is epigenetically silenced by EZH2-mediated H3K27me3, while loss-of-function mutations in FBXO32 cause dilated cardiomyopathy by impairing autophagy and activating CHOP-mediated apoptosis."},"narrative":{"mechanistic_narrative":"FBXO32 (Atrogin-1/MAFbx) is a muscle-enriched F-box protein that nucleates an SCF (Skp1-Cul1-Roc1) E3 ubiquitin ligase complex through its F-box domain and directs polyubiquitination of diverse substrates for proteasomal degradation, thereby governing skeletal and cardiac muscle protein homeostasis, autophagy, and cell growth [PMID:11717410]. In atrophying muscle it degrades myogenic regulators MyoD (via ubiquitination at K133) and myogenin, and the translation initiation factor eIF3-f (at conserved C-terminal lysines), coupling the ubiquitin-proteasome system to suppression of differentiation and growth; ubiquitination-resistant substrate mutants produce hypertrophy and resist atrophy [PMID:15531760, PMID:18354498, PMID:19073596, PMID:19319192, PMID:19631210]. Its transcription is the principal control node: FOXO3/FOXO4 factors activate the promoter and are repressed by IGF-1/PI3K/Akt signaling, while p38β MAPK phosphorylates C/EBPβ at Thr-188 to drive promoter binding during inflammatory and cachectic wasting, and Smad3 (downstream of TGF-β/myostatin and Pak1) activates the promoter to inhibit mTOR-dependent protein synthesis [PMID:15109499, PMID:15100091, PMID:21847090, PMID:23046544, PMID:18701653, PMID:24002653, PMID:26483344]. In the heart, FBXO32 maintains proteostasis and autophagy by degrading the ESCRT component CHMP2B and restrains calcineurin/NFAT-driven hypertrophy, and loss-of-function mutations that disrupt SCF assembly cause dilated cardiomyopathy through impaired autophagy and CHOP-mediated apoptosis [PMID:24789905, PMID:24650875, PMID:26753747, PMID:34272480]. Beyond muscle, FBXO32 ubiquitinates substrates including c-Myc, KLF4, CtBP1, and PHPT1 to control proliferation, epithelial-mesenchymal transition, and tumor growth, and its expression is epigenetically silenced by EZH2-mediated H3K27me3 [PMID:25944903, PMID:29142217, PMID:28068319, PMID:35411430, PMID:24213577].","teleology":[{"year":2001,"claim":"Established that FBXO32 is not merely a muscle-atrophy marker but a bona fide E3 ligase scaffold, defining the molecular machinery through which it acts.","evidence":"Molecular cloning and co-immunoprecipitation of Skp1, Roc1, and Cul1 with the F-box domain","pmids":["11717410"],"confidence":"High","gaps":["No substrate identified at this stage","Role of the NLS and PDZ-binding domain in function not resolved"]},{"year":2004,"claim":"Answered how upstream growth signaling controls FBXO32, placing it as the transcriptional output of FOXO downstream of IGF-1/PI3K/Akt during atrophy.","evidence":"Promoter reporter, constitutively active and dominant-negative Foxo3, in vivo RNAi, and PI3K/Akt inhibitor dissection in mouse muscle and myotubes","pmids":["15109499","15100091"],"confidence":"High","gaps":["Did not address parallel inflammatory inputs to the promoter","Direct FOXO binding sites partially defined"]},{"year":2004,"claim":"Provided the first reconstituted demonstration that SCF(MAFbx) is a functional ligase against a defined substrate, linking it mechanistically to suppression of myogenic differentiation.","evidence":"In vitro ubiquitination with purified recombinant SCF(MAFbx), MyoD K133 mutagenesis, LXXLL-motif interaction mapping, and myoblast overexpression","pmids":["15531760"],"confidence":"High","gaps":["In vivo relevance of K133 ubiquitination addressed only later","Other myogenic substrates not yet defined"]},{"year":2005,"claim":"Identified p38 MAPK as a distinct, Akt-independent route to FBXO32 induction, explaining inflammatory cytokine-driven atrophy.","evidence":"Pharmacological inhibitor dissection (p38 vs ERK/JNK) in C2C12 myotubes plus in vivo TNF-α injection","pmids":["15746179"],"confidence":"High","gaps":["Transcription factor linking p38 to the promoter not identified here"]},{"year":2008,"claim":"Expanded the substrate repertoire to the translation apparatus, showing FBXO32 controls muscle size by degrading eIF3-f and mapping the specific lysines required.","evidence":"Overexpression/shRNA, Co-IP, proteasome rescue, deletion and lysine mutagenesis (K5-10R), and in vivo hypertrophy assays","pmids":["18354498","19073596"],"confidence":"High","gaps":["Direct in vitro reconstitution of eIF3-f ubiquitination limited","Interplay with MyoD degradation not resolved"]},{"year":2008,"claim":"Extended FBXO32 function to cardiac stress signaling by identifying MKP-1 as a substrate whose degradation sustains JNK-driven cardiomyocyte apoptosis, and added a Foxo4-dependent transcriptional input.","evidence":"Co-IP, proteasome and JNK inhibitor rescues in cardiomyocytes; siRNA against Foxo4 in C2C12 myotubes","pmids":["19117950","18701653"],"confidence":"Medium","gaps":["No in vitro reconstitution of MKP-1 ubiquitination","Foxo4 mechanism shown without reciprocal validation"]},{"year":2009,"claim":"Consolidated FBXO32 as the degrader of myogenic transcription factors in vivo, demonstrating MyoD and myogenin degradation drive atrophy and that nuclear shuttling targets these substrates.","evidence":"shRNA knockdown, subcellular fractionation, in vivo MyoD K133R rescue, Co-IP and proteasome rescue for myogenin","pmids":["19319192","19631210"],"confidence":"High","gaps":["Signals controlling MAFbx nuclear-cytoplasmic shuttling unknown","Myogenin ubiquitination not reconstituted"]},{"year":2009,"claim":"Implicated FBXO32 in cardiac sarcomere quality control by showing selective degradation of truncated but not wild-type cMyBP-C.","evidence":"Adenoviral overexpression in cardiac myocytes, Co-IP, proteasome inhibitor rescue","pmids":["19850579"],"confidence":"Medium","gaps":["Single lab, no in vitro reconstitution","Mechanism of selectivity for truncated substrate unresolved"]},{"year":2011,"claim":"Linked FBXO32 to drug-induced and cancer-associated wasting, identifying statin sensitivity via geranylgeranylation and pinning C/EBPβ as the p38-driven promoter activator in cachexia.","evidence":"Atrogin-1 null cells, zebrafish knockdown, geranylgeraniol rescue; promoter reporter, ChIP, C/EBPβ KO mice, p38 inhibitor","pmids":["17992259","19406843","21847090"],"confidence":"High","gaps":["Statin-relevant FBXO32 substrate not defined","How geranylgeranylation feeds into FBXO32 induction unclear"]},{"year":2013,"claim":"Resolved the molecular switch coupling p38 to the FBXO32 promoter, showing p38β specifically phosphorylates C/EBPβ at Thr-188 to enable DNA binding.","evidence":"Tryptic phosphopeptide mapping, C/EBPβ T188A mutagenesis, ChIP, p38α/β siRNA, in vivo TA injection","pmids":["23046544"],"confidence":"High","gaps":["Single lab","Integration with FOXO inputs at the promoter not mapped"]},{"year":2013,"claim":"Identified Smad3/TGF-β signaling as an additional atrophic input acting on the FBXO32 promoter and coordinately suppressing Akt/mTOR protein synthesis.","evidence":"In vivo plasmid transfection, promoter reporter, protein synthesis and mTOR pathway analysis","pmids":["24002653"],"confidence":"Medium","gaps":["miR-29/PTEN link proposed without direct validation","Direct Smad3 promoter binding site defined only later"]},{"year":2014,"claim":"Defined FBXO32's cardioprotective role through proteostasis, showing CHMP2B degradation maintains autophagy and that suppression of calcineurin restrains hypertrophy during unloading.","evidence":"Atrogin-1 KO mice, pulsed SILAC proteomics, Co-IP, CHMP2B siRNA rescue; heterotopic transplantation, NFAT reporter, calcineurin inhibitor rescue","pmids":["24789905","24650875"],"confidence":"High","gaps":["Whether CHMP2B and calcineurin are degraded by the same SCF activity not distinguished","Direct in vitro ubiquitination not shown"]},{"year":2015,"claim":"Extended FBXO32 beyond muscle to growth control and cardiac transcriptional regulation, identifying c-Myc as a substrate in a negative-feedback loop and a Pak1/Smad3 promoter circuit.","evidence":"Co-IP, ubiquitination assay, c-Myc K326R mutagenesis, reporter assays; Pak1 KO mice, ChIP of Smad3 at FBXO32 promoter, berberine rescue","pmids":["25944903","26483344"],"confidence":"Medium","gaps":["c-Myc work single lab without in vitro reconstitution","Tissue contexts of the c-Myc feedback loop not defined"]},{"year":2016,"claim":"Broadened FBXO32 into oncogenic signaling and established the disease mechanism, showing it stabilizes CtBP1 to drive EMT and that an SCF-disrupting missense mutation causes dilated cardiomyopathy via impaired autophagy.","evidence":"Co-IP, ubiquitination, fractionation, xenograft for CtBP1; whole-exome sequencing and Co-IP from patient heart tissue for the cardiomyopathy mutation","pmids":["29142217","26753747"],"confidence":"Medium","gaps":["CtBP1 stabilization via ubiquitination mechanistically unusual and single-lab","Cardiomyopathy mutation from a single family"]},{"year":2016,"claim":"Revealed a membrane-trafficking and autophagy-biogenesis role independent of classic degradation, showing FBXO32 binds endophilin-A, tubulates membranes, and is required for autophagosome formation.","evidence":"Co-IP, live-cell imaging on clathrin structures and autophagosomes, overexpression/rescue, autophagy flux assays in neurons","pmids":["27720640"],"confidence":"Medium","gaps":["Whether E3 activity is required for membrane tubulation unclear","Single lab"]},{"year":2017,"claim":"Added KLF4 as a tumor-relevant substrate, mapping the interaction domains and linking degradation to p38 signaling and tumor growth.","evidence":"Genome-wide E3 ligase siRNA screen, Co-IP, domain mapping, ubiquitination assay, p38 inhibitor, in vivo tumor assay","pmids":["28068319"],"confidence":"Medium","gaps":["No in vitro reconstitution","Context determining oncogenic vs tumor-suppressive role unresolved"]},{"year":2021,"claim":"Mechanistically connected FBXO32 mutation to cardiomyocyte death, identifying ATF2 as a heart substrate whose impaired ubiquitination drives CHOP-mediated apoptosis.","evidence":"Co-IP of ATF2 with FBXO32 from human heart, ubiquitination assay, mutant overexpression, transcriptional profiling","pmids":["34272480"],"confidence":"Medium","gaps":["Single lab with limited replication","Non-canonical CHOP induction pathway not fully defined"]},{"year":2021,"claim":"Suggested a degradation-independent transcriptional regulatory function by showing FBXO32 partners with the chromatin remodeler SMARCA4 at regulated loci.","evidence":"Co-IP, proteomics, ChIP at FBXO32-regulated loci, transcriptomics after knockdown, in vivo tumor model","pmids":["33462405"],"confidence":"Medium","gaps":["Whether FBXO32 ubiquitinates SMARCA4 or acts as a cofactor unclear","Single lab"]},{"year":2022,"claim":"Identified PHPT1 as a substrate whose stabilization upon FBXO32 loss activates ERK/MAPK to promote lung cancer proliferation.","evidence":"Co-IP, mass spectrometry, siRNA knockdown, in vitro and in vivo tumor growth assays","pmids":["35411430"],"confidence":"Medium","gaps":["No in vitro reconstitution","Single lab"]},{"year":2011,"claim":"Established that FBXO32 expression is epigenetically gated, with EZH2-mediated H3K27me3 silencing its pro-apoptotic function in rhabdomyosarcoma, and HDAC1 controlling its atrophic induction.","evidence":"EZH2 siRNA and inhibitor, FBXO32 promoter ChIP for H3K27me3/EZH2, FBXO32 overexpression, in vivo tumor growth; HDAC1 inhibitor in hindlimb-unloaded rats","pmids":["24213577","31311969"],"confidence":"Medium","gaps":["Direct chromatin targeting of the FBXO32 locus context-specific","How epigenetic and transcription-factor inputs are integrated unknown"]},{"year":null,"claim":"It remains unresolved how FBXO32 selects among its many reported substrates across muscle, cardiac, neuronal, and cancer contexts, and which degradation-independent activities (membrane tubulation, chromatin association) require its E3 ligase function.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying substrate-recognition code defined","Tissue-specific substrate prioritization unknown","Structural basis of SCF(MAFbx)-substrate engagement not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,6,8,14,16,17,20,27]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,5,8,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14,18,19]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[8,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,12,13,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,14,25]}],"complexes":["SCF (Skp1-Cul1-Roc1-FBXO32) E3 ubiquitin ligase"],"partners":["SKP1","CUL1","RBX1","MYOD1","EIF3F","CHMP2B","SH3GL2","SMARCA4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969P5","full_name":"F-box only protein 32","aliases":["Atrogin-1","Muscle atrophy F-box protein","MAFbx"],"length_aa":355,"mass_kda":41.6,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. 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that binds Skp1, and thereby associates with Roc1 and Cul1 to form an SCF-type E3 ubiquitin ligase complex; it also contains a nuclear localization sequence and PDZ-binding domain.\",\n      \"method\": \"Molecular cloning, domain identification, co-immunoprecipitation with SCF complex components (Skp1, Roc1, Cul1)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding partners identified by Co-IP and functional domain confirmed; foundational paper replicated extensively\",\n      \"pmids\": [\"11717410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Foxo3 transcription factor acts on the atrogin-1 promoter to drive its transcription; PI3K/AKT pathway activation inhibits Foxo factors and thereby suppresses atrogin-1 expression. Dominant-negative Foxo or RNAi knockdown of Foxo in vivo prevents starvation-induced atrogin-1 induction and muscle atrophy.\",\n      \"method\": \"Promoter reporter assay, constitutively active Foxo3 overexpression, dominant-negative Foxo construct, RNAi in mouse muscles in vivo, IGF-1/AKT overexpression\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (promoter assay, gain-of-function, loss-of-function in cells and in vivo), widely replicated\",\n      \"pmids\": [\"15109499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The purified recombinant SCF(MAFbx) complex ubiquitinates MyoD in vitro in a lysine-dependent manner; mutation of lysine 133 in MyoD prevents its ubiquitination by SCF(MAFbx). MAFbx binds MyoD through an LXXLL motif in MyoD and an inverted LXXLL motif in MAFbx. Overexpression of MAFbx suppresses MyoD-induced differentiation and myotube formation.\",\n      \"method\": \"In vitro ubiquitination reconstitution with purified recombinant SCF(MAFbx), site-directed mutagenesis of MyoD K133, co-immunoprecipitation, overexpression in myoblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis confirming specific ubiquitination site; mechanistic detail confirmed by multiple orthogonal methods in one study\",\n      \"pmids\": [\"15531760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IGF-1 suppresses atrogin-1 expression by blocking mRNA synthesis (not by affecting mRNA degradation) through the PI3K/Akt pathway. Inhibition of PI3K-Akt (but not calcineurin-NFAT or MEK-ERK) increased atrogin-1 mRNA and proteolysis.\",\n      \"method\": \"mRNA stability assay, PI3K/Akt pathway inhibition, pathway-specific inhibitors, myotube culture\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pathway inhibitors used to dissect transcriptional mechanism, replicated across labs\",\n      \"pmids\": [\"15100091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TNF-α induces atrogin-1/MAFbx expression in skeletal muscle via p38 MAPK signaling; p38 inhibitors (SB203580, curcumin) blunt the TNF-α-induced increase in atrogin-1 mRNA and ubiquitin conjugating activity, whereas ERK and JNK inhibitors do not.\",\n      \"method\": \"Pharmacological inhibitors of p38, ERK, JNK in C2C12 myotubes; in vivo TNF-α injection in mice; ubiquitin conjugating activity assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dissection of specific MAPK pathway using multiple inhibitors in vitro and in vivo, replicated across models\",\n      \"pmids\": [\"15746179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"eIF3-f (eukaryotic initiation factor 3 subunit 5) is a direct substrate of MAFbx/Atrogin-1; MAFbx polyubiquitinates eIF3-f targeting it for proteasomal degradation. Blockade of MAFbx by shRNA prevents eIF3-f degradation during atrophy, and genetic activation of eIF3-f is sufficient to cause hypertrophy and block atrophy in myotubes.\",\n      \"method\": \"Ectopic MAFbx overexpression in myotubes, shRNA knockdown, co-immunoprecipitation, proteasome inhibitor rescue, in vivo hypertrophy assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (overexpression, RNAi, rescue experiments) in cells and in vivo, well-replicated substrate identification\",\n      \"pmids\": [\"18354498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAFbx/Atrogin-1 polyubiquitinates eIF3-f at multiple C-terminal lysine residues (six lysines in the conserved C-terminal domain are required for full polyubiquitination and degradation). Mutation of all six lysines (K5-10R mutant) produces a hypertrophic gain-of-function in cells and in vivo and protects against starvation-induced atrophy.\",\n      \"method\": \"Deletion analysis, site-directed mutagenesis of eIF3-f lysines, in vitro ubiquitination, in vivo overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination with mutagenesis identifying specific ubiquitination sites, validated in vivo, single lab\",\n      \"pmids\": [\"19073596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Atrogin-1/MAFbx interacts with and ubiquitinates MAPK phosphatase-1 (MKP-1), targeting it for proteasomal degradation. Loss of MKP-1 leads to sustained JNK activation and enhanced cardiomyocyte apoptosis following simulated ischemia/reperfusion.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor rescue of MKP-1 degradation, JNK inhibitor (SP600125) rescue assay, overexpression in cardiomyocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP confirmed interaction and proteasome inhibitor confirmed degradation pathway, but single lab with no in vitro reconstitution\",\n      \"pmids\": [\"19117950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAFbx targets MyoD for degradation in multiple skeletal muscle atrophy models; MAFbx undergoes cytoplasmic-nuclear shuttling during atrophy and selectively suppresses MyoD. shRNA-mediated MAFbx silencing inhibits MyoD proteolysis. Overexpression of a ubiquitination-deficient MyoD mutant (K133R) prevents atrophy of mouse primary myotubes and skeletal muscle fibers in vivo.\",\n      \"method\": \"shRNA knockdown of MAFbx in myotubes, subcellular fractionation/localization, overexpression of MyoDK133R mutant in vivo, protein degradation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo rescue with ubiquitination-deficient mutant, multiple atrophy models, RNAi validation; replicates prior in vitro ubiquitination finding\",\n      \"pmids\": [\"19319192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAFbx/Atrogin-1 is identified as the F-box protein responsible for polyubiquitination of myogenin in atrophying myotubes; MAFbx overexpression causes MG132-sensitive (proteasome-dependent) reduction of myogenin. Myogenin contains a MAFbx-recognition motif and physically interacts with MAFbx.\",\n      \"method\": \"Co-immunoprecipitation, overexpression with proteasome inhibitor rescue, myogenin ubiquitination assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and proteasome inhibitor rescue, single lab, no full in vitro reconstitution\",\n      \"pmids\": [\"19631210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Atrogin-1 co-immunoprecipitates with truncated (M7t) but not wild-type cardiac myosin-binding protein C (cMyBP-C); overexpression of atrogin-1 decreases M7t-cMyBP-C protein level by ~80% in a proteasome-dependent manner, while leaving wild-type cMyBP-C unaffected.\",\n      \"method\": \"Adenoviral overexpression in cardiac myocytes, co-immunoprecipitation, proteasome inhibitor rescue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and proteasome inhibitor rescue in primary cardiomyocytes, single lab\",\n      \"pmids\": [\"19850579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Atrogin-1/MAFbx mediates statin-induced muscle damage; lovastatin induces atrogin-1 expression in humans, zebrafish, and mouse myotubes. atrogin-1 null cells are largely spared from lovastatin-induced morphological changes; atrogin-1 knockdown in zebrafish prevents lovastatin-induced muscle fiber damage. Statin damage is linked to inhibition of geranylgeranylation, not cholesterol synthesis.\",\n      \"method\": \"Atrogin-1 null cell lines, zebrafish knockdown, lovastatin treatment, geranylgeraniol/farnesol rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null cells, zebrafish knockdown, and pharmacological rescue across three model systems\",\n      \"pmids\": [\"17992259\", \"19406843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C/EBPβ is activated downstream of p38 MAPK and binds a specific C/EBPβ-responsive cis-element in the atrogin-1/MAFbx gene promoter to drive its transcription during cancer cachexia. p38α/β MAPK inhibitor blocks C/EBPβ binding and atrogin-1 induction; C/EBPβ-knockout mice are resistant to LLC tumor-induced atrogin-1 upregulation and muscle wasting.\",\n      \"method\": \"Promoter reporter assay, chromatin immunoprecipitation, C/EBPβ knockout mice, p38 MAPK inhibitor, siRNA knockdown in C2C12 myotubes\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, promoter assay, KO mice, and chemical inhibition used; in vivo validation in tumour-bearing mice\",\n      \"pmids\": [\"21847090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p38β MAPK, but not p38α, specifically phosphorylates C/EBPβ at Thr-188, which is critical for C/EBPβ DNA-binding activity and subsequent binding to the atrogin-1/MAFbx promoter. A C/EBPβ T188A dominant-negative mutant blocks atrogin-1 upregulation; this effect is absent in C/EBPβ-null mice.\",\n      \"method\": \"Tryptic phosphopeptide mapping, chromatin immunoprecipitation, site-directed mutagenesis of C/EBPβ, siRNA knockdown of p38α/β, in vivo tibialis anterior injection\",\n      \"journal\": \"Skeletal muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — phosphopeptide mapping identifying specific phosphorylation site combined with mutagenesis, ChIP, and in vivo validation; single lab\",\n      \"pmids\": [\"23046544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Atrogin-1 targets CHMP2B (charged multivesicular body protein 2B, a component of the ESCRT autophagy complex) for ubiquitin-mediated degradation. Loss of atrogin-1 in KO mice causes CHMP2B accumulation, impaired autophagy, intracellular protein aggregate accumulation, UPR activation, cardiomyocyte apoptosis, and progressive cardiomyopathy. CHMP2B downregulation in atrogin-1 KO mice restores autophagy.\",\n      \"method\": \"Atrogin-1 KO mice, in vivo pulsed SILAC proteomics, co-immunoprecipitation, biochemical fractionation, CHMP2B siRNA rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with proteomics substrate identification, Co-IP confirmation, and rescue experiment; rigorous multi-method study\",\n      \"pmids\": [\"24789905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart; MAFbx/Atrogin-1 KO hearts undergo hypertrophy instead of atrophy following mechanical unloading (heterotopic transplantation). In KO hearts, calcineurin accumulates and NFAT transcriptional activity and protein synthesis rates are increased; calcineurin inhibition normalizes NFAT activity. MAFbx/Atrogin-1 thus suppresses calcineurin-driven hypertrophy during unloading.\",\n      \"method\": \"MAFbx/Atrogin-1 KO mice, heterotopic heart transplantation model, calcineurin protein measurement, NFAT luciferase reporter, protein synthesis measurement, calcineurin inhibitor rescue\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with mechanistic pathway (calcineurin/NFAT) identified and rescued by inhibitor; validated in human LVAD samples\",\n      \"pmids\": [\"24650875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXO32/Atrogin-1 targets c-Myc for ubiquitination and proteasomal degradation; mutation of lysine 326 in c-Myc reduces ubiquitination and prevents FBXO32-induced degradation. Phosphorylation of c-Myc at Thr-58/Ser-62 is dispensable for FBXO32-mediated degradation. FBXO32 is itself a direct transcriptional target of c-Myc, creating a negative feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (c-Myc K326R), luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis identifying ubiquitination site, reporter assay for negative feedback; single lab\",\n      \"pmids\": [\"25944903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXO32 directly ubiquitinates CtBP1, which is required for CtBP1 stability and nuclear retention, enabling epigenetic remodeling and transcriptional induction of CtBP1 target genes that promote epithelial-mesenchymal transition (EMT). FBXO32 knockdown inhibits tumor growth and metastasis in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear/cytoplasmic fractionation, NSG mouse xenograft, transcriptomic analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay confirmed CtBP1 as substrate; in vivo xenograft confirms functional role; single lab\",\n      \"pmids\": [\"29142217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A missense mutation in FBXO32 impairs binding to SCF complex proteins (validated by co-immunoprecipitation in cells expressing mutant protein and in patient heart tissue), leading to autophagy impairment and dilated cardiomyopathy. Patient hearts show accumulation of proteins regulating autophagy.\",\n      \"method\": \"Co-immunoprecipitation from patient heart tissue and transfected cells, whole exome sequencing, protein accumulation assay\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from patient tissue validates functional consequence of mutation; single family with limited replication\",\n      \"pmids\": [\"26753747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXO32/Atrogin-1 interacts with all three endophilin-A proteins; FBXO32 overexpression triggers apoptosis in neurons, but co-expression of endophilin-A rescues this. FBXO32 tubulates membranes and localizes on clathrin-coated structures and transiently co-localizes with autophagosomes. Both FBXO32 and endophilin-A are required for autophagosome formation.\",\n      \"method\": \"Co-immunoprecipitation, live cell imaging (localization on clathrin-coated structures and autophagosomes), overexpression/rescue experiments, autophagy flux assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interactions, live imaging established localization; rescue experiment demonstrated functional relationship; single lab\",\n      \"pmids\": [\"27720640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXO32 physically interacts with the N-terminus (1–60 aa) of KLF4 via its C-terminus (228–355 aa), and the F-box domain is required for FBXO32-dependent KLF4 ubiquitination and degradation. p38 MAPK pathway activity is implicated in this process, as p38 inhibitor abrogates KLF4 ubiquitination.\",\n      \"method\": \"Genome-wide E3 ligase siRNA screen, co-immunoprecipitation, domain mapping, ubiquitination assay, p38 inhibitor treatment, in vivo tumor growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen followed by Co-IP and domain mapping; ubiquitination assay confirmed; single lab\",\n      \"pmids\": [\"28068319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TNF-α increases nuclear Foxo4 protein and atrogin-1 mRNA independently of AKT and Foxo1/Foxo3; siRNA against Foxo4 reduces the TNF-induced increase in atrogin-1 mRNA. TNF does not affect Foxo1/3 nuclear localization despite increasing atrogin-1 expression.\",\n      \"method\": \"PI3K inhibitor (wortmannin), siRNA against Foxo4, IGF stimulation, subcellular fractionation, qRT-PCR in C2C12 myotubes\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with nuclear localization assay; single lab, limited orthogonal methods\",\n      \"pmids\": [\"18701653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Smad3 is sufficient to stimulate atrogin-1 promoter activity, inhibit Akt/mTOR signaling and protein synthesis, and induce muscle fiber atrophy in vivo. Smad3-induced inhibition of mTOR is proposed to occur via reduced miR-29 expression and increased PTEN translation.\",\n      \"method\": \"In vivo plasmid transfection (transient transgenic mouse muscle), promoter reporter assay, protein synthesis measurement, mTOR pathway analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transfection with promoter reporter and functional phenotype; single lab\",\n      \"pmids\": [\"24002653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXO3a mediates crosstalk between PI3K/Akt and MEK/ERK pathways to coordinate atrogin-1 and ubiquitin expression; knockdown of IRS-1 or constitutively active FOXO3a increases IRS-2 protein, MEK/ERK signaling, and ubiquitin expression, linking the two atrogene transcription programs.\",\n      \"method\": \"siRNA knockdown of IRS-1, adenovirus-mediated constitutively active FOXO3a expression, Western blotting, streptozotocin diabetes rat model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation (siRNA, adenovirus) in cells and in vivo rat model; single lab\",\n      \"pmids\": [\"20371624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pak1 activation under pressure overload upregulates Fbxo32 expression through Smad3 binding to an AGAC(-286) site on the FBXO32 promoter. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling in cardiac-specific Pak1 KO mice.\",\n      \"method\": \"Cardiac-specific Pak1 KO mice, constitutively active Pak1 overexpression, chromatin immunoprecipitation (Smad3 binding to FBXO32 promoter), promoter mutagenesis, berberine treatment\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed specific Smad3 binding site on FBXO32 promoter; KO mouse and pharmacological rescue validate pathway; single lab\",\n      \"pmids\": [\"26483344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant FBXO32 impairs ATF2 ubiquitination; ATF2 protein physically interacts with FBXO32 in the human heart, and expression of mutant FBXO32 is sufficient to induce CHOP-associated apoptosis. FBXO32 mutation causes up-regulation of CHOP and its target genes through a non-canonical pathway.\",\n      \"method\": \"Co-immunoprecipitation of ATF2 with FBXO32 from human heart, ubiquitination assay, overexpression of mutant FBXO32 in cells, transcriptional profiling\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from patient heart tissue, ubiquitination assay, functional overexpression; single lab, limited replication\",\n      \"pmids\": [\"34272480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Atrogin-1-mediated ubiquitination of aquaporin 4 (AQP4) targets it for degradation in atrophying muscle; AQP4 knockdown reduces myotube size. HMGB1 acts upstream of atrogin-1 via NF-κB signaling to increase atrogin-1 expression.\",\n      \"method\": \"Ubiquitination assay after AQP4 immunoprecipitation, AQP4 knockdown in myotubes, recombinant HMGB1 treatment, NF-κB pathway analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination assay after immunoprecipitation confirmed AQP4 as substrate; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"32843684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO32 acts as an E3 ubiquitin ligase for PHPT1; knockdown of FBXO32 leads to PHPT1 accumulation and activation of the ERK/MAPK pathway, promoting lung cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, western blotting, siRNA knockdown of FBXO32, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and mass spectrometry identified substrate; knockdown confirmed pathway activation; single lab\",\n      \"pmids\": [\"35411430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO32 and SMARCA4 (a component of the BAF/PBAF chromatin remodeling complex) physically interact; FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32 (e.g., CDK6), suggesting FBXO32 controls transcription through regulation of chromatin remodeling complex activity. FBXO32 is identified as a MITF target gene.\",\n      \"method\": \"Co-immunoprecipitation, proteomic analysis, ChIP at FBXO32-regulated loci, transcriptomic analysis after FBXO32 knockdown, in vivo tumor model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed SMARCA4 as partner; ChIP showed co-localization at target loci; single lab\",\n      \"pmids\": [\"33462405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EZH2 represses FBXO32 transcription via H3K27 trimethylation at the FBXO32 promoter in PAX3-FOXO1 alveolar rhabdomyosarcoma; EZH2 depletion causes transcriptional derepression of FBXO32 and FBXO32-dependent apoptosis. Simultaneous knockdown of FBXO32 and EZH2 impairs the pro-apoptotic response.\",\n      \"method\": \"EZH2 siRNA knockdown, FBXO32 promoter ChIP for H3K27me3 and EZH2 occupancy, overexpression of FBXO32, pharmacological EZH2 inhibition, in vivo tumor growth\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed epigenetic repression mechanism; genetic and pharmacological rescue validated in vivo; single lab\",\n      \"pmids\": [\"24213577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Atrogin-1/MAFbx mRNA expression in rat soleus muscle under hindlimb unloading is regulated by HDAC1; pharmacological inhibition of HDAC1 (CI-994) prevents the unloading-induced increase in MAFbx and ubiquitin expression, without affecting MuRF-1 expression.\",\n      \"method\": \"HDAC1 inhibitor CI-994 treatment in hindlimb-suspended rats, nuclear fractionation of HDAC1, RT-PCR, Western blotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological inhibition with subcellular fractionation; specific to MAFbx but not MuRF1; single lab\",\n      \"pmids\": [\"31311969\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO32/Atrogin-1/MAFbx is a muscle-enriched F-box protein that assembles into an SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase complex; it polyubiquitinates multiple substrates—including MyoD (at K133), myogenin, eIF3-f (at C-terminal lysines), MKP-1, CHMP2B, calcineurin, cMyBP-C (truncated mutants), AQP4, KLF4, c-Myc, CtBP1, PHPT1, and ATF2—targeting them for proteasomal degradation, thereby regulating skeletal and cardiac muscle protein homeostasis, autophagy flux, cell growth, and epithelial–mesenchymal transition; its transcription is controlled by FOXO transcription factors downstream of PI3K/Akt, by p38β MAPK-phosphorylated C/EBPβ binding to its promoter, by Smad3 (downstream of Pak1 or TGF-β/myostatin), and is epigenetically silenced by EZH2-mediated H3K27me3, while loss-of-function mutations in FBXO32 cause dilated cardiomyopathy by impairing autophagy and activating CHOP-mediated apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO32 (Atrogin-1/MAFbx) is a muscle-enriched F-box protein that nucleates an SCF (Skp1-Cul1-Roc1) E3 ubiquitin ligase complex through its F-box domain and directs polyubiquitination of diverse substrates for proteasomal degradation, thereby governing skeletal and cardiac muscle protein homeostasis, autophagy, and cell growth [#0]. In atrophying muscle it degrades myogenic regulators MyoD (via ubiquitination at K133) and myogenin, and the translation initiation factor eIF3-f (at conserved C-terminal lysines), coupling the ubiquitin-proteasome system to suppression of differentiation and growth; ubiquitination-resistant substrate mutants produce hypertrophy and resist atrophy [#2, #5, #6, #8, #9]. Its transcription is the principal control node: FOXO3/FOXO4 factors activate the promoter and are repressed by IGF-1/PI3K/Akt signaling, while p38β MAPK phosphorylates C/EBPβ at Thr-188 to drive promoter binding during inflammatory and cachectic wasting, and Smad3 (downstream of TGF-β/myostatin and Pak1) activates the promoter to inhibit mTOR-dependent protein synthesis [#1, #3, #12, #13, #21, #22, #24]. In the heart, FBXO32 maintains proteostasis and autophagy by degrading the ESCRT component CHMP2B and restrains calcineurin/NFAT-driven hypertrophy, and loss-of-function mutations that disrupt SCF assembly cause dilated cardiomyopathy through impaired autophagy and CHOP-mediated apoptosis [#14, #15, #18, #25]. Beyond muscle, FBXO32 ubiquitinates substrates including c-Myc, KLF4, CtBP1, and PHPT1 to control proliferation, epithelial-mesenchymal transition, and tumor growth, and its expression is epigenetically silenced by EZH2-mediated H3K27me3 [#16, #17, #20, #27, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that FBXO32 is not merely a muscle-atrophy marker but a bona fide E3 ligase scaffold, defining the molecular machinery through which it acts.\",\n      \"evidence\": \"Molecular cloning and co-immunoprecipitation of Skp1, Roc1, and Cul1 with the F-box domain\",\n      \"pmids\": [\"11717410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate identified at this stage\", \"Role of the NLS and PDZ-binding domain in function not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Answered how upstream growth signaling controls FBXO32, placing it as the transcriptional output of FOXO downstream of IGF-1/PI3K/Akt during atrophy.\",\n      \"evidence\": \"Promoter reporter, constitutively active and dominant-negative Foxo3, in vivo RNAi, and PI3K/Akt inhibitor dissection in mouse muscle and myotubes\",\n      \"pmids\": [\"15109499\", \"15100091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address parallel inflammatory inputs to the promoter\", \"Direct FOXO binding sites partially defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the first reconstituted demonstration that SCF(MAFbx) is a functional ligase against a defined substrate, linking it mechanistically to suppression of myogenic differentiation.\",\n      \"evidence\": \"In vitro ubiquitination with purified recombinant SCF(MAFbx), MyoD K133 mutagenesis, LXXLL-motif interaction mapping, and myoblast overexpression\",\n      \"pmids\": [\"15531760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of K133 ubiquitination addressed only later\", \"Other myogenic substrates not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified p38 MAPK as a distinct, Akt-independent route to FBXO32 induction, explaining inflammatory cytokine-driven atrophy.\",\n      \"evidence\": \"Pharmacological inhibitor dissection (p38 vs ERK/JNK) in C2C12 myotubes plus in vivo TNF-α injection\",\n      \"pmids\": [\"15746179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor linking p38 to the promoter not identified here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Expanded the substrate repertoire to the translation apparatus, showing FBXO32 controls muscle size by degrading eIF3-f and mapping the specific lysines required.\",\n      \"evidence\": \"Overexpression/shRNA, Co-IP, proteasome rescue, deletion and lysine mutagenesis (K5-10R), and in vivo hypertrophy assays\",\n      \"pmids\": [\"18354498\", \"19073596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro reconstitution of eIF3-f ubiquitination limited\", \"Interplay with MyoD degradation not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended FBXO32 function to cardiac stress signaling by identifying MKP-1 as a substrate whose degradation sustains JNK-driven cardiomyocyte apoptosis, and added a Foxo4-dependent transcriptional input.\",\n      \"evidence\": \"Co-IP, proteasome and JNK inhibitor rescues in cardiomyocytes; siRNA against Foxo4 in C2C12 myotubes\",\n      \"pmids\": [\"19117950\", \"18701653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of MKP-1 ubiquitination\", \"Foxo4 mechanism shown without reciprocal validation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Consolidated FBXO32 as the degrader of myogenic transcription factors in vivo, demonstrating MyoD and myogenin degradation drive atrophy and that nuclear shuttling targets these substrates.\",\n      \"evidence\": \"shRNA knockdown, subcellular fractionation, in vivo MyoD K133R rescue, Co-IP and proteasome rescue for myogenin\",\n      \"pmids\": [\"19319192\", \"19631210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling MAFbx nuclear-cytoplasmic shuttling unknown\", \"Myogenin ubiquitination not reconstituted\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Implicated FBXO32 in cardiac sarcomere quality control by showing selective degradation of truncated but not wild-type cMyBP-C.\",\n      \"evidence\": \"Adenoviral overexpression in cardiac myocytes, Co-IP, proteasome inhibitor rescue\",\n      \"pmids\": [\"19850579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no in vitro reconstitution\", \"Mechanism of selectivity for truncated substrate unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked FBXO32 to drug-induced and cancer-associated wasting, identifying statin sensitivity via geranylgeranylation and pinning C/EBPβ as the p38-driven promoter activator in cachexia.\",\n      \"evidence\": \"Atrogin-1 null cells, zebrafish knockdown, geranylgeraniol rescue; promoter reporter, ChIP, C/EBPβ KO mice, p38 inhibitor\",\n      \"pmids\": [\"17992259\", \"19406843\", \"21847090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Statin-relevant FBXO32 substrate not defined\", \"How geranylgeranylation feeds into FBXO32 induction unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the molecular switch coupling p38 to the FBXO32 promoter, showing p38β specifically phosphorylates C/EBPβ at Thr-188 to enable DNA binding.\",\n      \"evidence\": \"Tryptic phosphopeptide mapping, C/EBPβ T188A mutagenesis, ChIP, p38α/β siRNA, in vivo TA injection\",\n      \"pmids\": [\"23046544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Integration with FOXO inputs at the promoter not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified Smad3/TGF-β signaling as an additional atrophic input acting on the FBXO32 promoter and coordinately suppressing Akt/mTOR protein synthesis.\",\n      \"evidence\": \"In vivo plasmid transfection, promoter reporter, protein synthesis and mTOR pathway analysis\",\n      \"pmids\": [\"24002653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"miR-29/PTEN link proposed without direct validation\", \"Direct Smad3 promoter binding site defined only later\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined FBXO32's cardioprotective role through proteostasis, showing CHMP2B degradation maintains autophagy and that suppression of calcineurin restrains hypertrophy during unloading.\",\n      \"evidence\": \"Atrogin-1 KO mice, pulsed SILAC proteomics, Co-IP, CHMP2B siRNA rescue; heterotopic transplantation, NFAT reporter, calcineurin inhibitor rescue\",\n      \"pmids\": [\"24789905\", \"24650875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHMP2B and calcineurin are degraded by the same SCF activity not distinguished\", \"Direct in vitro ubiquitination not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended FBXO32 beyond muscle to growth control and cardiac transcriptional regulation, identifying c-Myc as a substrate in a negative-feedback loop and a Pak1/Smad3 promoter circuit.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, c-Myc K326R mutagenesis, reporter assays; Pak1 KO mice, ChIP of Smad3 at FBXO32 promoter, berberine rescue\",\n      \"pmids\": [\"25944903\", \"26483344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"c-Myc work single lab without in vitro reconstitution\", \"Tissue contexts of the c-Myc feedback loop not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened FBXO32 into oncogenic signaling and established the disease mechanism, showing it stabilizes CtBP1 to drive EMT and that an SCF-disrupting missense mutation causes dilated cardiomyopathy via impaired autophagy.\",\n      \"evidence\": \"Co-IP, ubiquitination, fractionation, xenograft for CtBP1; whole-exome sequencing and Co-IP from patient heart tissue for the cardiomyopathy mutation\",\n      \"pmids\": [\"29142217\", \"26753747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CtBP1 stabilization via ubiquitination mechanistically unusual and single-lab\", \"Cardiomyopathy mutation from a single family\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a membrane-trafficking and autophagy-biogenesis role independent of classic degradation, showing FBXO32 binds endophilin-A, tubulates membranes, and is required for autophagosome formation.\",\n      \"evidence\": \"Co-IP, live-cell imaging on clathrin structures and autophagosomes, overexpression/rescue, autophagy flux assays in neurons\",\n      \"pmids\": [\"27720640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E3 activity is required for membrane tubulation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Added KLF4 as a tumor-relevant substrate, mapping the interaction domains and linking degradation to p38 signaling and tumor growth.\",\n      \"evidence\": \"Genome-wide E3 ligase siRNA screen, Co-IP, domain mapping, ubiquitination assay, p38 inhibitor, in vivo tumor assay\",\n      \"pmids\": [\"28068319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution\", \"Context determining oncogenic vs tumor-suppressive role unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistically connected FBXO32 mutation to cardiomyocyte death, identifying ATF2 as a heart substrate whose impaired ubiquitination drives CHOP-mediated apoptosis.\",\n      \"evidence\": \"Co-IP of ATF2 with FBXO32 from human heart, ubiquitination assay, mutant overexpression, transcriptional profiling\",\n      \"pmids\": [\"34272480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with limited replication\", \"Non-canonical CHOP induction pathway not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Suggested a degradation-independent transcriptional regulatory function by showing FBXO32 partners with the chromatin remodeler SMARCA4 at regulated loci.\",\n      \"evidence\": \"Co-IP, proteomics, ChIP at FBXO32-regulated loci, transcriptomics after knockdown, in vivo tumor model\",\n      \"pmids\": [\"33462405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBXO32 ubiquitinates SMARCA4 or acts as a cofactor unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified PHPT1 as a substrate whose stabilization upon FBXO32 loss activates ERK/MAPK to promote lung cancer proliferation.\",\n      \"evidence\": \"Co-IP, mass spectrometry, siRNA knockdown, in vitro and in vivo tumor growth assays\",\n      \"pmids\": [\"35411430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that FBXO32 expression is epigenetically gated, with EZH2-mediated H3K27me3 silencing its pro-apoptotic function in rhabdomyosarcoma, and HDAC1 controlling its atrophic induction.\",\n      \"evidence\": \"EZH2 siRNA and inhibitor, FBXO32 promoter ChIP for H3K27me3/EZH2, FBXO32 overexpression, in vivo tumor growth; HDAC1 inhibitor in hindlimb-unloaded rats\",\n      \"pmids\": [\"24213577\", \"31311969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targeting of the FBXO32 locus context-specific\", \"How epigenetic and transcription-factor inputs are integrated unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how FBXO32 selects among its many reported substrates across muscle, cardiac, neuronal, and cancer contexts, and which degradation-independent activities (membrane tubulation, chromatin association) require its E3 ligase function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying substrate-recognition code defined\", \"Tissue-specific substrate prioritization unknown\", \"Structural basis of SCF(MAFbx)-substrate engagement not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 6, 8, 14, 16, 17, 20, 27]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 5, 8, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14, 18, 19]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 12, 13, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 14, 25]}\n    ],\n    \"complexes\": [\"SCF (Skp1-Cul1-Roc1-FBXO32) E3 ubiquitin ligase\"],\n    \"partners\": [\"SKP1\", \"CUL1\", \"RBX1\", \"MYOD1\", \"EIF3F\", \"CHMP2B\", \"SH3GL2\", \"SMARCA4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}