{"gene":"ARMC5","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2013,"finding":"ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival, establishing ARMC5 as a putative tumor suppressor gene in adrenocortical cells.","method":"Cell-culture models with ARMC5 inactivation and overexpression","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in cell culture with defined phenotypic readouts (steroidogenesis, cell survival), single lab, two orthogonal functional assays","pmids":["24283224"],"is_preprint":false},{"year":2015,"finding":"ARMC5 missense mutants and the p.F700del deletion are unable to induce apoptosis in H295R and HeLa cell lines, unlike wild-type ARMC5, demonstrating that ARMC5 promotes apoptosis and disease-associated mutations abrogate this function.","method":"Overexpression of wild-type and mutant ARMC5 in H295R and HeLa cells with apoptosis assays","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression assay in two cell lines with defined apoptosis readout, single lab, mutant vs. wild-type comparison","pmids":["25853793"],"is_preprint":false},{"year":2017,"finding":"Armc5 knockout mice die during early embryonic development around E6.5–E8.5 and fail to undergo gastrulation (absence of mesoderm at E7.5), establishing an essential role for ARMC5 in early embryonic development.","method":"Armc5 knockout mouse model with histological analysis at E7.5","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with clear developmental phenotype, confirmed by histology, replicated at multiple time points","pmids":["28911199"],"is_preprint":false},{"year":2017,"finding":"Armc5 haploinsufficiency (Armc5+/- mice) leads to age-dependent decrease in corticosterone associated with decreased PKA catalytic subunit α (Cα) expression, followed later by hypercorticosteronemia with increased PKA/Cα expression and abnormal activation of Wnt/β-catenin signaling in zona fasciculata cells.","method":"Armc5 heterozygous mouse model with hormone measurements, RNA/protein expression analysis, and adrenocortical tissue immunohistochemistry at multiple ages","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with longitudinal analysis, multiple molecular readouts (PKA, Wnt/β-catenin), confirmed in human PMAH patient tissue","pmids":["28911199"],"is_preprint":false},{"year":2017,"finding":"Armc5 deletion in mice compromises T-cell proliferation, differentiation into Th1 and Th17 cells, and increases T-cell apoptosis, establishing a role for ARMC5 in T-cell immune responses.","method":"Armc5 knockout mouse model with T-cell proliferation assays, differentiation assays, and apoptosis measurements; in vivo infection models (EAE, LCMV)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple orthogonal immune phenotype readouts across different experimental models","pmids":["28169274"],"is_preprint":false},{"year":2017,"finding":"Yeast 2-hybrid assays identified 16 ARMC5-binding partners, establishing that ARMC5 functions through interaction with multiple signaling pathway proteins.","method":"Yeast 2-hybrid assay","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast 2-hybrid screen without validation of individual interactions by orthogonal methods; partners not individually confirmed","pmids":["28169274"],"is_preprint":false},{"year":2017,"finding":"ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related gene expression and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability, while ARMC5 overexpression induced cell death in PMAH-mutated cell cultures.","method":"siRNA silencing and overexpression in primary PMAH cell cultures with RT-PCR, proliferation, and viability assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function in disease-relevant primary cell cultures with multiple molecular and phenotypic readouts, single lab","pmids":["28676429"],"is_preprint":false},{"year":2020,"finding":"ARMC5 interacts with CUL3 via its BTB domain; this interaction leads to ARMC5 ubiquitination and proteasomal degradation. ARMC5 alters cell cycle progression (G1/S phases and cyclin E accumulation), and this effect is blocked by CUL3. BTB-domain missense mutations found in patients abolish CUL3 interaction and ARMC5 degradation.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, flow cytometry cell cycle analysis, mutant ARMC5 expression in cell lines","journal":"Endocrine-related cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing direct CUL3 interaction via BTB domain, functional consequence (cell cycle), patient mutation validation abrogating interaction, multiple orthogonal methods","pmids":["32023208"],"is_preprint":false},{"year":2021,"finding":"USP7 interacts with ARMC5 in vivo and in vitro, deubiquitinates ARMC5, and stabilizes it via the ubiquitin-proteasome pathway; USP7-mediated ARMC5 stabilization regulates G1/S cell cycle transition and renal cancer cell proliferation.","method":"Co-immunoprecipitation, deubiquitinase library screen, Western blot, overexpression and knockdown assays in renal cancer cells","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in vivo and in vitro, overexpression/knockdown with defined phenotypic readouts, single lab","pmids":["33544460"],"is_preprint":false},{"year":2022,"finding":"ARMC5 functions as a substrate adaptor in a CUL3-RBX1 E3 ubiquitin ligase complex that ubiquitinates RPB1 (the largest subunit of RNA Pol II). ARMC5 deletion reduces RPB1 ubiquitination and causes accumulation of RPB1 and an enlarged Pol II pool, dysregulating a subset of genes. Mutant ARMC5 from PBMAH patients shows altered binding with RPB1.","method":"Co-immunoprecipitation, ubiquitination assays in vitro and in cells, Armc5 knockout mice with RPB1 protein quantification, RNA-seq transcriptome analysis, patient sample immunohistochemistry","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — active E3 ligase complex reconstituted, ubiquitination assay, in vivo knockout validation, multiple orthogonal methods across mouse and human samples","pmids":["35687106"],"is_preprint":false},{"year":2022,"finding":"ARMC5 interacts with full-length SREBF (SREBP) through its Armadillo repeat domain and with CUL3 through its BTB domain, and promotes proteasome-dependent degradation of full-length SREBF via ubiquitination. ARMC5 missense mutations in its Armadillo repeat attenuate SREBF interaction; BMAH-associated mutations abolish SREBF degradation. In H295R cells, ARMC5 silencing increases full-length SREBFs and upregulates SREBF2 target genes; ARMC5-siRNA-mediated cell growth is abrogated by simultaneous SREBF2 knockdown.","method":"Biochemical purification with SREBF as bait, Co-IP, colocalization assays, proteasome inhibitor treatment, siRNA knockdown in H295R cells, mutant ARMC5 expression","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification identifying interaction, functional ubiquitination/degradation assay, domain mapping, patient mutation validation, rescue experiment with SREBF2 knockdown, multiple orthogonal methods","pmids":["35862218"],"is_preprint":false},{"year":2022,"finding":"ARMC5 is involved in NRF1 ubiquitination and controls NRF1 half-life in adrenocortical cells. ARMC5 inactivation increases NRF1 expression, elevates antioxidant enzymes (SODs and peroxiredoxins), alters adrenocortical steroidogenesis via the p38 pathway, decreases cell sensitivity to ferroptosis, and increases cell viability.","method":"siRNA knockdown in adrenocortical cells, ubiquitination assays, half-life measurements, Western blot for NRF1/SOD/PRDX, p38 pathway inhibitor studies, ferroptosis sensitivity assays","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular readouts from loss-of-function with mechanistic pathway placement, single lab","pmids":["36040830"],"is_preprint":false},{"year":2024,"finding":"CRL3ARMC5 targets excessive and defective RNA Pol II at initial stages of the transcription cycle (promoter-proximal zone and free pool). Upon ARMC5 loss, RNA Pol II accumulates in the free pool and promoter-proximal zone but is not released into elongation. Integrator subunit 8 (INTS8) acts as a gatekeeper preventing release of excess Pol II into gene bodies. Combined loss of ARMC5 and INTS8 leads to uncontrolled release of transcriptionally incompetent Pol II into early elongation, with detrimental effects on cell growth.","method":"ARMC5 knockout and INTS8 knockout human cells, ChIP-seq, RNA-seq, genome-wide Pol II occupancy analysis, cell growth assays, double-mutant epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — genome-wide mechanistic analysis with epistasis (double KO), multiple orthogonal genomics and cell biology methods, clear pathway placement","pmids":["39667934"],"is_preprint":false},{"year":2024,"finding":"ARMC5 controls degradation of not only POLR2A but also most of the other 11 Pol II subunits, indicating ARMC5-dependent E3 ligase activity controls degradation of the entire Pol II complex. ARMC5 knockout dysregulates 106 genes in neural progenitor cells including FOLH1. ARMC5 mutations identified in spina bifida patients impair ARMC5 interaction with Pol II and reduce Pol II ubiquitination.","method":"Armc5 knockout mice with proteomic quantification of all Pol II subunits, RNA-seq in neural progenitor cells, ubiquitination assays, Co-IP with patient mutants, NTD incidence scoring","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo knockout with proteomics of all Pol II subunits, ubiquitination assay, mutant interaction studies, replicated across cell and animal models","pmids":["38225631"],"is_preprint":false},{"year":2025,"finding":"ARMC5 acts as a CUL3 adaptor targeting promoter-proximal, chromatin-bound Pol II lacking SPT5 for VCP/p97-dependent degradation. ARMC5 targets promoter-proximal Pol II in a BTB domain-dependent manner. Interaction between ARMC5 and Pol II requires CDK9, supporting a phospho-dependent degradation model.","method":"Unbiased proteomic screening, genome-wide ChIP analysis, Co-IP, biochemical interaction assays with CDK9 inhibitors, BTB domain mutants","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — unbiased proteomic identification, biochemical domain mapping, genome-wide ChIP, CDK9 phospho-dependency experiment, multiple orthogonal methods","pmids":["39854452"],"is_preprint":false},{"year":2024,"finding":"ARMC5 selectively degrades SCAP-free full-length SREBF1 (but not SCAP-associated SREBF1) and is essential for fatty acid desaturation in adipocytes. Adipocyte-specific Armc5 KO mice show dramatic downregulation of all stearoyl-CoA desaturases (Scd), decreased unsaturated fatty acids, increased saturated fatty acids, and paradoxically diminished SREBF1 transcriptional activity at Scd1 locus despite increased full-length SREBF1 protein.","method":"Adipocyte-specific Armc5 KO mice, ATAC-seq, fatty acid composition analysis, Armc5-deficient 3T3-L1 adipocytes, CHO cells with Scap deficiency, SCAP overexpression competition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo tissue-specific KO with ATAC-seq and lipidomics, mechanistic rescue experiments with SCAP competition, multiple orthogonal model systems","pmids":["39491648"],"is_preprint":false}],"current_model":"ARMC5 is a cytosolic armadillo repeat- and BTB domain-containing protein that functions as a substrate adaptor within a CUL3-RBX1 E3 ubiquitin ligase complex, directing ubiquitination and proteasomal degradation of multiple substrates including all 12 subunits of RNA Polymerase II (particularly promoter-proximal, CDK9-phosphorylated, SPT5-deficient Pol II), full-length SREBF/SREBP transcription factors (selectively the SCAP-free pool), and the transcriptional regulator NRF1; it is stabilized by the deubiquitinase USP7, is itself ubiquitinated and degraded by CUL3, is essential for early embryonic development and T-cell function in mice, acts as a tumor suppressor in adrenocortical cells by promoting apoptosis and restraining cell cycle progression, and its inactivating mutations cause primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by enlarging the Pol II pool and dysregulating a subset of effector genes including those controlling steroidogenesis."},"narrative":{"mechanistic_narrative":"ARMC5 is a cytosolic armadillo repeat- and BTB domain-containing substrate adaptor for a CUL3-RBX1 E3 ubiquitin ligase that directs ubiquitination and proteasomal degradation of selected substrates to control transcriptional capacity and cell fate [PMID:35687106, PMID:35862218]. Its principal substrate is RNA Polymerase II: CRL3-ARMC5 ubiquitinates RPB1/POLR2A and, in fact, all twelve Pol II subunits, restraining the cellular Pol II pool such that ARMC5 loss causes RPB1 accumulation and dysregulation of a defined subset of effector genes [PMID:35687106, PMID:38225631]. ARMC5 selectively recognizes excess and defective promoter-proximal, chromatin-bound Pol II that is CDK9-phosphorylated and SPT5-deficient, engaging this pool through its BTB domain and targeting it for VCP/p97-dependent degradation, while the Integrator gatekeeper INTS8 cooperates to prevent release of transcriptionally incompetent Pol II into elongation [PMID:39667934, PMID:39854452]. Beyond Pol II, ARMC5 uses its armadillo repeat domain to bind and degrade the SCAP-free pool of full-length SREBF/SREBP transcription factors, governing SREBF2 target genes in adrenocortical cells and stearoyl-CoA desaturase-driven fatty acid desaturation in adipocytes, and it controls the half-life of the antioxidant regulator NRF1 [PMID:35862218, PMID:39491648, PMID:36040830]. ARMC5 is itself a CUL3 substrate, interacting with CUL3 via its BTB domain and undergoing CUL3-dependent ubiquitination and degradation, and is stabilized by the deubiquitinase USP7 [PMID:32023208, PMID:33544460]. Functionally, ARMC5 is essential for early mouse embryonic development and gastrulation, supports T-cell proliferation and Th1/Th17 differentiation, and acts as an adrenocortical tumor suppressor by promoting apoptosis and restraining cell-cycle progression, with patient-derived inactivating mutations in the BTB or armadillo domains abrogating CUL3 binding, substrate binding, and degradation activity [PMID:28911199, PMID:28169274, PMID:32023208, PMID:35862218]. Inactivating ARMC5 mutations cause primary bilateral macronodular adrenocortical hyperplasia by enlarging the Pol II pool and dysregulating steroidogenic effector genes [PMID:35687106, PMID:28911199].","teleology":[{"year":2013,"claim":"Established ARMC5 as a candidate adrenocortical tumor suppressor, the first functional clue to its biological role.","evidence":"ARMC5 inactivation and overexpression in adrenocortical cell-culture models scoring steroidogenesis and cell survival","pmids":["24283224"],"confidence":"Medium","gaps":["No molecular mechanism for tumor suppression","No substrate or pathway identified","Single lab cell-culture phenotype"]},{"year":2015,"claim":"Showed that ARMC5 promotes apoptosis and that disease-associated mutations abolish this activity, linking loss of function to disease.","evidence":"Overexpression of wild-type vs mutant (missense, p.F700del) ARMC5 in H295R and HeLa cells with apoptosis assays","pmids":["25853793"],"confidence":"Medium","gaps":["Mechanism connecting ARMC5 to apoptosis machinery unknown","Overexpression-based readout","No endogenous-level validation"]},{"year":2017,"claim":"Defined ARMC5's organismal requirements — embryonic gastrulation, adrenal steroidogenesis/Wnt signaling, and T-cell immunity — placing it in development and immune function.","evidence":"Armc5 knockout and heterozygous mice with histology, hormone and PKA/Wnt readouts, and T-cell proliferation/differentiation/apoptosis assays in EAE and LCMV models","pmids":["28911199","28169274"],"confidence":"High","gaps":["Molecular substrate driving these phenotypes not yet identified","Connection between adrenal and immune roles unclear","Causal mediator of Wnt/PKA changes undefined"]},{"year":2017,"claim":"Provided first interactome and disease-relevant cell evidence, hinting ARMC5 acts through multiple protein partners while confirming proliferative/steroidogenic control in PMAH cells.","evidence":"Yeast 2-hybrid screen identifying 16 binding partners; siRNA and overexpression in primary PMAH cell cultures","pmids":["28169274","28676429"],"confidence":"Low","gaps":["Y2H interactions not validated by orthogonal methods","Individual partners not functionally confirmed","Biochemical activity of ARMC5 still unknown"]},{"year":2020,"claim":"Identified ARMC5 as a CUL3 partner via its BTB domain, revealing it is itself an E3 ligase substrate and connecting it to cell-cycle control and patient mutations.","evidence":"Reciprocal Co-IP, proteasome inhibition, flow-cytometry cell cycle analysis, and BTB-mutant expression in cell lines","pmids":["32023208"],"confidence":"High","gaps":["Whether ARMC5 acts as adaptor versus substrate of CUL3 not resolved here","Functional substrates of an ARMC5-CUL3 complex unknown","Mechanism linking CUL3 to cyclin E unclear"]},{"year":2021,"claim":"Showed USP7 deubiquitinates and stabilizes ARMC5, establishing post-translational regulation of ARMC5 abundance with cell-cycle and proliferation consequences.","evidence":"Deubiquitinase library screen, Co-IP in vivo and in vitro, knockdown/overexpression in renal cancer cells","pmids":["33544460"],"confidence":"Medium","gaps":["Physiological context of USP7-ARMC5 regulation beyond renal cancer cells unclear","Single lab","Whether USP7 regulates ARMC5 substrate output not tested"]},{"year":2022,"claim":"Resolved the central mechanism: ARMC5 is a CUL3-RBX1 substrate adaptor that ubiquitinates RNA Pol II (RPB1), with loss enlarging the Pol II pool and dysregulating genes, and disease mutants showing altered RPB1 binding.","evidence":"Co-IP, in vitro and cellular ubiquitination assays, Armc5 KO mice with RPB1 quantification, RNA-seq, and patient-sample IHC","pmids":["35687106"],"confidence":"High","gaps":["Which Pol II states are selected not yet defined","How enlarged Pol II pool causes specific gene dysregulation unclear","Other substrates not yet enumerated"]},{"year":2022,"claim":"Extended substrate range to SREBF and NRF1, showing ARMC5 uses distinct domains (Armadillo for SREBF, BTB for CUL3) to degrade lipogenic and antioxidant regulators.","evidence":"Biochemical purification with SREBF bait, Co-IP, colocalization, ubiquitination and half-life assays, siRNA and SREBF2-rescue in H295R and adrenocortical cells","pmids":["35862218","36040830"],"confidence":"High","gaps":["Selectivity rules distinguishing SREBF/NRF1 substrates from Pol II unknown","NRF1 work single lab/Medium confidence","Relative contribution of each substrate to PBMAH unresolved"]},{"year":2024,"claim":"Defined the Pol II degradation mechanism at genome scale: CRL3-ARMC5 clears excess/defective promoter-proximal and free-pool Pol II, with INTS8 acting as a release gatekeeper, and showed ARMC5 controls all 12 Pol II subunits with a human disease link to spina bifida.","evidence":"ARMC5/INTS8 KO human cells with ChIP-seq, RNA-seq, Pol II occupancy and epistasis; Armc5 KO mouse proteomics of all Pol II subunits; Co-IP with NTD patient mutants","pmids":["39667934","38225631"],"confidence":"High","gaps":["How ARMC5 distinguishes defective from productive Pol II not fully defined","Mechanistic relationship with INTS8 incompletely mapped","Generality of NTD association across patient cohorts limited"]},{"year":2025,"claim":"Pinpointed the molecular recognition signal: ARMC5 targets chromatin-bound, CDK9-phosphorylated, SPT5-deficient promoter-proximal Pol II for VCP/p97-dependent degradation in a BTB-dependent manner, defining a phospho-dependent degradation model.","evidence":"Unbiased proteomics, genome-wide ChIP, Co-IP with CDK9 inhibitors, BTB-domain mutants","pmids":["39854452"],"confidence":"High","gaps":["Direct phospho-mark read by ARMC5 not structurally defined","Interplay of CDK9 phosphorylation and SPT5 absence not fully dissected","Role of VCP/p97 versus proteasome partitioning unclear"]},{"year":2024,"claim":"Demonstrated tissue-specific substrate selectivity in lipid metabolism: ARMC5 degrades only the SCAP-free pool of full-length SREBF1, and is required for fatty acid desaturation in adipocytes.","evidence":"Adipocyte-specific Armc5 KO mice with ATAC-seq and lipidomics, 3T3-L1 adipocytes, CHO Scap-deficiency and SCAP competition assays","pmids":["39491648"],"confidence":"High","gaps":["Mechanism by which SCAP shields SREBF1 from ARMC5 not structurally resolved","Why increased full-length SREBF1 yields decreased transcriptional output unexplained","Link between adipocyte and adrenal substrate logic unclear"]},{"year":null,"claim":"How a single CUL3-ARMC5 adaptor achieves selectivity among structurally unrelated substrates (Pol II subunits, SREBF, NRF1) and how this maps onto the distinct developmental, immune, adrenal, and metabolic phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of ARMC5 substrate recognition","Substrate hierarchy/competition in different tissues unknown","Causal substrate(s) for each disease phenotype not isolated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,10,11,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,10,14]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[9,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,14]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,10,11,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,12,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,15]}],"complexes":["CUL3-RBX1 E3 ubiquitin ligase (CRL3-ARMC5)"],"partners":["CUL3","RBX1","POLR2A","USP7","SREBF1","NRF1","INTS8","CDK9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96C12","full_name":"Armadillo repeat-containing protein 5","aliases":[],"length_aa":935,"mass_kda":97.7,"function":"Substrate-recognition component of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes (PubMed:39504960, PubMed:39667934). The BCR(ARMC5) complex provides a quality checkpoint during transcription elongation by driving premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: the BCR(ARMC5) complex acts by mediating ubiquitination of Pol II subunit POLR2A phosphorylated at 'Ser-5' of the C-terminal domain (CTD), leading to POLR2A degradation (PubMed:35687106, PubMed:38225631, PubMed:39504960, PubMed:39667934). The BCR(ARMC5) complex acts in parallel of the integrator complex and is specific for RNA Pol II originating from the promoter-proximal zone: it does not ubiquitinate elongation-stalled RNA Pol II (PubMed:39667934). The BCR(ARMC5) complex also acts as a regulator of fatty acid desaturation by mediating ubiquitination and degradation of SCAP-free SREBF1 and SREBF2 (PubMed:35862218). Involved in fetal development, T-cell function and adrenal gland growth homeostasis (PubMed:24283224, PubMed:28676429). Plays a role in steroidogenesis, modulates steroidogenic enzymes expression and cortisol production (PubMed:24283224, PubMed:28676429)","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96C12/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMC5","classification":"Not Classified","n_dependent_lines":403,"n_total_lines":1208,"dependency_fraction":0.3336092715231788},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARMC5","total_profiled":1310},"omim":[{"mim_id":"615954","title":"ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA 2; AIMAH2","url":"https://www.omim.org/entry/615954"},{"mim_id":"615549","title":"ARMADILLO REPEAT-CONTAINING PROTEIN 5; ARMC5","url":"https://www.omim.org/entry/615549"},{"mim_id":"219080","title":"ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA 1; AIMAH1","url":"https://www.omim.org/entry/219080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARMC5"},"hgnc":{"alias_symbol":["FLJ13063"],"prev_symbol":[]},"alphafold":{"accession":"Q96C12","domains":[{"cath_id":"1.25.10.10","chopping":"41-75_124-224","consensus_level":"medium","plddt":94.4168,"start":41,"end":224},{"cath_id":"-","chopping":"525-713","consensus_level":"medium","plddt":89.8161,"start":525,"end":713},{"cath_id":"3.30.710.10","chopping":"742-826_840-845","consensus_level":"medium","plddt":90.6868,"start":742,"end":845}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96C12","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96C12-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96C12-F1-predicted_aligned_error_v6.png","plddt_mean":80.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMC5","jax_strain_url":"https://www.jax.org/strain/search?query=ARMC5"},"sequence":{"accession":"Q96C12","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96C12.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96C12/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96C12"}},"corpus_meta":[{"pmid":"24283224","id":"PMC_24283224","title":"ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome.","date":"2013","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24283224","citation_count":287,"is_preprint":false},{"pmid":"25853793","id":"PMC_25853793","title":"ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.","date":"2015","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25853793","citation_count":138,"is_preprint":false},{"pmid":"24601692","id":"PMC_24601692","title":"Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24601692","citation_count":125,"is_preprint":false},{"pmid":"24708098","id":"PMC_24708098","title":"ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24708098","citation_count":118,"is_preprint":false},{"pmid":"24905064","id":"PMC_24905064","title":"ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24905064","citation_count":96,"is_preprint":false},{"pmid":"25822102","id":"PMC_25822102","title":"Primary Aldosteronism and ARMC5 Variants.","date":"2015","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25822102","citation_count":87,"is_preprint":false},{"pmid":"25279498","id":"PMC_25279498","title":"Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma.","date":"2015","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25279498","citation_count":78,"is_preprint":false},{"pmid":"27094308","id":"PMC_27094308","title":"A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.","date":"2016","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/27094308","citation_count":64,"is_preprint":false},{"pmid":"35521700","id":"PMC_35521700","title":"Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients.","date":"2022","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35521700","citation_count":47,"is_preprint":false},{"pmid":"28911199","id":"PMC_28911199","title":"Age-dependent effects of Armc5 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inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival, establishing ARMC5 as a putative tumor suppressor gene in adrenocortical cells.\",\n      \"method\": \"Cell-culture models with ARMC5 inactivation and overexpression\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in cell culture with defined phenotypic readouts (steroidogenesis, cell survival), single lab, two orthogonal functional assays\",\n      \"pmids\": [\"24283224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ARMC5 missense mutants and the p.F700del deletion are unable to induce apoptosis in H295R and HeLa cell lines, unlike wild-type ARMC5, demonstrating that ARMC5 promotes apoptosis and disease-associated mutations abrogate this function.\",\n      \"method\": \"Overexpression of wild-type and mutant ARMC5 in H295R and HeLa cells with apoptosis assays\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression assay in two cell lines with defined apoptosis readout, single lab, mutant vs. wild-type comparison\",\n      \"pmids\": [\"25853793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Armc5 knockout mice die during early embryonic development around E6.5–E8.5 and fail to undergo gastrulation (absence of mesoderm at E7.5), establishing an essential role for ARMC5 in early embryonic development.\",\n      \"method\": \"Armc5 knockout mouse model with histological analysis at E7.5\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with clear developmental phenotype, confirmed by histology, replicated at multiple time points\",\n      \"pmids\": [\"28911199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Armc5 haploinsufficiency (Armc5+/- mice) leads to age-dependent decrease in corticosterone associated with decreased PKA catalytic subunit α (Cα) expression, followed later by hypercorticosteronemia with increased PKA/Cα expression and abnormal activation of Wnt/β-catenin signaling in zona fasciculata cells.\",\n      \"method\": \"Armc5 heterozygous mouse model with hormone measurements, RNA/protein expression analysis, and adrenocortical tissue immunohistochemistry at multiple ages\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with longitudinal analysis, multiple molecular readouts (PKA, Wnt/β-catenin), confirmed in human PMAH patient tissue\",\n      \"pmids\": [\"28911199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Armc5 deletion in mice compromises T-cell proliferation, differentiation into Th1 and Th17 cells, and increases T-cell apoptosis, establishing a role for ARMC5 in T-cell immune responses.\",\n      \"method\": \"Armc5 knockout mouse model with T-cell proliferation assays, differentiation assays, and apoptosis measurements; in vivo infection models (EAE, LCMV)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple orthogonal immune phenotype readouts across different experimental models\",\n      \"pmids\": [\"28169274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Yeast 2-hybrid assays identified 16 ARMC5-binding partners, establishing that ARMC5 functions through interaction with multiple signaling pathway proteins.\",\n      \"method\": \"Yeast 2-hybrid assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast 2-hybrid screen without validation of individual interactions by orthogonal methods; partners not individually confirmed\",\n      \"pmids\": [\"28169274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related gene expression and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability, while ARMC5 overexpression induced cell death in PMAH-mutated cell cultures.\",\n      \"method\": \"siRNA silencing and overexpression in primary PMAH cell cultures with RT-PCR, proliferation, and viability assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function in disease-relevant primary cell cultures with multiple molecular and phenotypic readouts, single lab\",\n      \"pmids\": [\"28676429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARMC5 interacts with CUL3 via its BTB domain; this interaction leads to ARMC5 ubiquitination and proteasomal degradation. ARMC5 alters cell cycle progression (G1/S phases and cyclin E accumulation), and this effect is blocked by CUL3. BTB-domain missense mutations found in patients abolish CUL3 interaction and ARMC5 degradation.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, flow cytometry cell cycle analysis, mutant ARMC5 expression in cell lines\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing direct CUL3 interaction via BTB domain, functional consequence (cell cycle), patient mutation validation abrogating interaction, multiple orthogonal methods\",\n      \"pmids\": [\"32023208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP7 interacts with ARMC5 in vivo and in vitro, deubiquitinates ARMC5, and stabilizes it via the ubiquitin-proteasome pathway; USP7-mediated ARMC5 stabilization regulates G1/S cell cycle transition and renal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitinase library screen, Western blot, overexpression and knockdown assays in renal cancer cells\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in vivo and in vitro, overexpression/knockdown with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"33544460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARMC5 functions as a substrate adaptor in a CUL3-RBX1 E3 ubiquitin ligase complex that ubiquitinates RPB1 (the largest subunit of RNA Pol II). ARMC5 deletion reduces RPB1 ubiquitination and causes accumulation of RPB1 and an enlarged Pol II pool, dysregulating a subset of genes. Mutant ARMC5 from PBMAH patients shows altered binding with RPB1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays in vitro and in cells, Armc5 knockout mice with RPB1 protein quantification, RNA-seq transcriptome analysis, patient sample immunohistochemistry\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active E3 ligase complex reconstituted, ubiquitination assay, in vivo knockout validation, multiple orthogonal methods across mouse and human samples\",\n      \"pmids\": [\"35687106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARMC5 interacts with full-length SREBF (SREBP) through its Armadillo repeat domain and with CUL3 through its BTB domain, and promotes proteasome-dependent degradation of full-length SREBF via ubiquitination. ARMC5 missense mutations in its Armadillo repeat attenuate SREBF interaction; BMAH-associated mutations abolish SREBF degradation. In H295R cells, ARMC5 silencing increases full-length SREBFs and upregulates SREBF2 target genes; ARMC5-siRNA-mediated cell growth is abrogated by simultaneous SREBF2 knockdown.\",\n      \"method\": \"Biochemical purification with SREBF as bait, Co-IP, colocalization assays, proteasome inhibitor treatment, siRNA knockdown in H295R cells, mutant ARMC5 expression\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification identifying interaction, functional ubiquitination/degradation assay, domain mapping, patient mutation validation, rescue experiment with SREBF2 knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"35862218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARMC5 is involved in NRF1 ubiquitination and controls NRF1 half-life in adrenocortical cells. ARMC5 inactivation increases NRF1 expression, elevates antioxidant enzymes (SODs and peroxiredoxins), alters adrenocortical steroidogenesis via the p38 pathway, decreases cell sensitivity to ferroptosis, and increases cell viability.\",\n      \"method\": \"siRNA knockdown in adrenocortical cells, ubiquitination assays, half-life measurements, Western blot for NRF1/SOD/PRDX, p38 pathway inhibitor studies, ferroptosis sensitivity assays\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular readouts from loss-of-function with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"36040830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRL3ARMC5 targets excessive and defective RNA Pol II at initial stages of the transcription cycle (promoter-proximal zone and free pool). Upon ARMC5 loss, RNA Pol II accumulates in the free pool and promoter-proximal zone but is not released into elongation. Integrator subunit 8 (INTS8) acts as a gatekeeper preventing release of excess Pol II into gene bodies. Combined loss of ARMC5 and INTS8 leads to uncontrolled release of transcriptionally incompetent Pol II into early elongation, with detrimental effects on cell growth.\",\n      \"method\": \"ARMC5 knockout and INTS8 knockout human cells, ChIP-seq, RNA-seq, genome-wide Pol II occupancy analysis, cell growth assays, double-mutant epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genome-wide mechanistic analysis with epistasis (double KO), multiple orthogonal genomics and cell biology methods, clear pathway placement\",\n      \"pmids\": [\"39667934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARMC5 controls degradation of not only POLR2A but also most of the other 11 Pol II subunits, indicating ARMC5-dependent E3 ligase activity controls degradation of the entire Pol II complex. ARMC5 knockout dysregulates 106 genes in neural progenitor cells including FOLH1. ARMC5 mutations identified in spina bifida patients impair ARMC5 interaction with Pol II and reduce Pol II ubiquitination.\",\n      \"method\": \"Armc5 knockout mice with proteomic quantification of all Pol II subunits, RNA-seq in neural progenitor cells, ubiquitination assays, Co-IP with patient mutants, NTD incidence scoring\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo knockout with proteomics of all Pol II subunits, ubiquitination assay, mutant interaction studies, replicated across cell and animal models\",\n      \"pmids\": [\"38225631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARMC5 acts as a CUL3 adaptor targeting promoter-proximal, chromatin-bound Pol II lacking SPT5 for VCP/p97-dependent degradation. ARMC5 targets promoter-proximal Pol II in a BTB domain-dependent manner. Interaction between ARMC5 and Pol II requires CDK9, supporting a phospho-dependent degradation model.\",\n      \"method\": \"Unbiased proteomic screening, genome-wide ChIP analysis, Co-IP, biochemical interaction assays with CDK9 inhibitors, BTB domain mutants\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — unbiased proteomic identification, biochemical domain mapping, genome-wide ChIP, CDK9 phospho-dependency experiment, multiple orthogonal methods\",\n      \"pmids\": [\"39854452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARMC5 selectively degrades SCAP-free full-length SREBF1 (but not SCAP-associated SREBF1) and is essential for fatty acid desaturation in adipocytes. Adipocyte-specific Armc5 KO mice show dramatic downregulation of all stearoyl-CoA desaturases (Scd), decreased unsaturated fatty acids, increased saturated fatty acids, and paradoxically diminished SREBF1 transcriptional activity at Scd1 locus despite increased full-length SREBF1 protein.\",\n      \"method\": \"Adipocyte-specific Armc5 KO mice, ATAC-seq, fatty acid composition analysis, Armc5-deficient 3T3-L1 adipocytes, CHO cells with Scap deficiency, SCAP overexpression competition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo tissue-specific KO with ATAC-seq and lipidomics, mechanistic rescue experiments with SCAP competition, multiple orthogonal model systems\",\n      \"pmids\": [\"39491648\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMC5 is a cytosolic armadillo repeat- and BTB domain-containing protein that functions as a substrate adaptor within a CUL3-RBX1 E3 ubiquitin ligase complex, directing ubiquitination and proteasomal degradation of multiple substrates including all 12 subunits of RNA Polymerase II (particularly promoter-proximal, CDK9-phosphorylated, SPT5-deficient Pol II), full-length SREBF/SREBP transcription factors (selectively the SCAP-free pool), and the transcriptional regulator NRF1; it is stabilized by the deubiquitinase USP7, is itself ubiquitinated and degraded by CUL3, is essential for early embryonic development and T-cell function in mice, acts as a tumor suppressor in adrenocortical cells by promoting apoptosis and restraining cell cycle progression, and its inactivating mutations cause primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by enlarging the Pol II pool and dysregulating a subset of effector genes including those controlling steroidogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARMC5 is a cytosolic armadillo repeat- and BTB domain-containing substrate adaptor for a CUL3-RBX1 E3 ubiquitin ligase that directs ubiquitination and proteasomal degradation of selected substrates to control transcriptional capacity and cell fate [#9, #10]. Its principal substrate is RNA Polymerase II: CRL3-ARMC5 ubiquitinates RPB1/POLR2A and, in fact, all twelve Pol II subunits, restraining the cellular Pol II pool such that ARMC5 loss causes RPB1 accumulation and dysregulation of a defined subset of effector genes [#9, #13]. ARMC5 selectively recognizes excess and defective promoter-proximal, chromatin-bound Pol II that is CDK9-phosphorylated and SPT5-deficient, engaging this pool through its BTB domain and targeting it for VCP/p97-dependent degradation, while the Integrator gatekeeper INTS8 cooperates to prevent release of transcriptionally incompetent Pol II into elongation [#12, #14]. Beyond Pol II, ARMC5 uses its armadillo repeat domain to bind and degrade the SCAP-free pool of full-length SREBF/SREBP transcription factors, governing SREBF2 target genes in adrenocortical cells and stearoyl-CoA desaturase-driven fatty acid desaturation in adipocytes, and it controls the half-life of the antioxidant regulator NRF1 [#10, #15, #11]. ARMC5 is itself a CUL3 substrate, interacting with CUL3 via its BTB domain and undergoing CUL3-dependent ubiquitination and degradation, and is stabilized by the deubiquitinase USP7 [#7, #8]. Functionally, ARMC5 is essential for early mouse embryonic development and gastrulation, supports T-cell proliferation and Th1/Th17 differentiation, and acts as an adrenocortical tumor suppressor by promoting apoptosis and restraining cell-cycle progression, with patient-derived inactivating mutations in the BTB or armadillo domains abrogating CUL3 binding, substrate binding, and degradation activity [#2, #4, #7, #10]. Inactivating ARMC5 mutations cause primary bilateral macronodular adrenocortical hyperplasia by enlarging the Pol II pool and dysregulating steroidogenic effector genes [#9, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established ARMC5 as a candidate adrenocortical tumor suppressor, the first functional clue to its biological role.\",\n      \"evidence\": \"ARMC5 inactivation and overexpression in adrenocortical cell-culture models scoring steroidogenesis and cell survival\",\n      \"pmids\": [\"24283224\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular mechanism for tumor suppression\", \"No substrate or pathway identified\", \"Single lab cell-culture phenotype\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that ARMC5 promotes apoptosis and that disease-associated mutations abolish this activity, linking loss of function to disease.\",\n      \"evidence\": \"Overexpression of wild-type vs mutant (missense, p.F700del) ARMC5 in H295R and HeLa cells with apoptosis assays\",\n      \"pmids\": [\"25853793\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism connecting ARMC5 to apoptosis machinery unknown\", \"Overexpression-based readout\", \"No endogenous-level validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined ARMC5's organismal requirements — embryonic gastrulation, adrenal steroidogenesis/Wnt signaling, and T-cell immunity — placing it in development and immune function.\",\n      \"evidence\": \"Armc5 knockout and heterozygous mice with histology, hormone and PKA/Wnt readouts, and T-cell proliferation/differentiation/apoptosis assays in EAE and LCMV models\",\n      \"pmids\": [\"28911199\", \"28169274\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular substrate driving these phenotypes not yet identified\", \"Connection between adrenal and immune roles unclear\", \"Causal mediator of Wnt/PKA changes undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided first interactome and disease-relevant cell evidence, hinting ARMC5 acts through multiple protein partners while confirming proliferative/steroidogenic control in PMAH cells.\",\n      \"evidence\": \"Yeast 2-hybrid screen identifying 16 binding partners; siRNA and overexpression in primary PMAH cell cultures\",\n      \"pmids\": [\"28169274\", \"28676429\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Y2H interactions not validated by orthogonal methods\", \"Individual partners not functionally confirmed\", \"Biochemical activity of ARMC5 still unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified ARMC5 as a CUL3 partner via its BTB domain, revealing it is itself an E3 ligase substrate and connecting it to cell-cycle control and patient mutations.\",\n      \"evidence\": \"Reciprocal Co-IP, proteasome inhibition, flow-cytometry cell cycle analysis, and BTB-mutant expression in cell lines\",\n      \"pmids\": [\"32023208\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether ARMC5 acts as adaptor versus substrate of CUL3 not resolved here\", \"Functional substrates of an ARMC5-CUL3 complex unknown\", \"Mechanism linking CUL3 to cyclin E unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed USP7 deubiquitinates and stabilizes ARMC5, establishing post-translational regulation of ARMC5 abundance with cell-cycle and proliferation consequences.\",\n      \"evidence\": \"Deubiquitinase library screen, Co-IP in vivo and in vitro, knockdown/overexpression in renal cancer cells\",\n      \"pmids\": [\"33544460\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological context of USP7-ARMC5 regulation beyond renal cancer cells unclear\", \"Single lab\", \"Whether USP7 regulates ARMC5 substrate output not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the central mechanism: ARMC5 is a CUL3-RBX1 substrate adaptor that ubiquitinates RNA Pol II (RPB1), with loss enlarging the Pol II pool and dysregulating genes, and disease mutants showing altered RPB1 binding.\",\n      \"evidence\": \"Co-IP, in vitro and cellular ubiquitination assays, Armc5 KO mice with RPB1 quantification, RNA-seq, and patient-sample IHC\",\n      \"pmids\": [\"35687106\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Which Pol II states are selected not yet defined\", \"How enlarged Pol II pool causes specific gene dysregulation unclear\", \"Other substrates not yet enumerated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended substrate range to SREBF and NRF1, showing ARMC5 uses distinct domains (Armadillo for SREBF, BTB for CUL3) to degrade lipogenic and antioxidant regulators.\",\n      \"evidence\": \"Biochemical purification with SREBF bait, Co-IP, colocalization, ubiquitination and half-life assays, siRNA and SREBF2-rescue in H295R and adrenocortical cells\",\n      \"pmids\": [\"35862218\", \"36040830\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Selectivity rules distinguishing SREBF/NRF1 substrates from Pol II unknown\", \"NRF1 work single lab/Medium confidence\", \"Relative contribution of each substrate to PBMAH unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the Pol II degradation mechanism at genome scale: CRL3-ARMC5 clears excess/defective promoter-proximal and free-pool Pol II, with INTS8 acting as a release gatekeeper, and showed ARMC5 controls all 12 Pol II subunits with a human disease link to spina bifida.\",\n      \"evidence\": \"ARMC5/INTS8 KO human cells with ChIP-seq, RNA-seq, Pol II occupancy and epistasis; Armc5 KO mouse proteomics of all Pol II subunits; Co-IP with NTD patient mutants\",\n      \"pmids\": [\"39667934\", \"38225631\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How ARMC5 distinguishes defective from productive Pol II not fully defined\", \"Mechanistic relationship with INTS8 incompletely mapped\", \"Generality of NTD association across patient cohorts limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pinpointed the molecular recognition signal: ARMC5 targets chromatin-bound, CDK9-phosphorylated, SPT5-deficient promoter-proximal Pol II for VCP/p97-dependent degradation in a BTB-dependent manner, defining a phospho-dependent degradation model.\",\n      \"evidence\": \"Unbiased proteomics, genome-wide ChIP, Co-IP with CDK9 inhibitors, BTB-domain mutants\",\n      \"pmids\": [\"39854452\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct phospho-mark read by ARMC5 not structurally defined\", \"Interplay of CDK9 phosphorylation and SPT5 absence not fully dissected\", \"Role of VCP/p97 versus proteasome partitioning unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated tissue-specific substrate selectivity in lipid metabolism: ARMC5 degrades only the SCAP-free pool of full-length SREBF1, and is required for fatty acid desaturation in adipocytes.\",\n      \"evidence\": \"Adipocyte-specific Armc5 KO mice with ATAC-seq and lipidomics, 3T3-L1 adipocytes, CHO Scap-deficiency and SCAP competition assays\",\n      \"pmids\": [\"39491648\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which SCAP shields SREBF1 from ARMC5 not structurally resolved\", \"Why increased full-length SREBF1 yields decreased transcriptional output unexplained\", \"Link between adipocyte and adrenal substrate logic unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single CUL3-ARMC5 adaptor achieves selectivity among structurally unrelated substrates (Pol II subunits, SREBF, NRF1) and how this maps onto the distinct developmental, immune, adrenal, and metabolic phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of ARMC5 substrate recognition\", \"Substrate hierarchy/competition in different tissues unknown\", \"Causal substrate(s) for each disease phenotype not isolated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 10, 11, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 10, 14]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 10, 11, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 12, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"complexes\": [\"CUL3-RBX1 E3 ubiquitin ligase (CRL3-ARMC5)\"],\n    \"partners\": [\"CUL3\", \"RBX1\", \"POLR2A\", \"USP7\", \"SREBF1\", \"NRF1\", \"INTS8\", \"CDK9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}