{"gene":"YDJC","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"Crystal structure of the YdjC-family protein TTHB029 (Thermus thermophilus) was determined at 2.9 Å resolution, revealing a (βα)-barrel fold homodimer with Asp21, His60, and His127 coordinating Mg²⁺ as the probable active site, and structural similarity to peptidoglycan N-acetylglucosamine deacetylase (SpPgdA); the Asp-His-His metal-binding triad is fully conserved across the YdjC family including human YDJC.","method":"X-ray crystallography at 2.9 Å resolution with structural comparison","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with active-site identification and cross-family conservation analysis; single study but direct structural determination","pmids":["18177738"],"is_preprint":false},{"year":2012,"finding":"The bacterial ydjC homolog chbG encodes a monodeacetylase essential for growth on acetylated chitooligosaccharides (chitobiose, chitotriose); substitution of conserved metal-binding residues abolished activity, validating the predicted active site; deacetylation of chitobiose-6-P and chitotriose-6-P by ChbG is required for their recognition as inducers by the regulatory protein ChbR.","method":"Growth assays, loss-of-function mutagenesis of active-site residues, genetic epistasis with chbR mutations","journal":"Journal of bacteriology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic activity demonstrated with active-site mutagenesis plus genetic epistasis; single lab but multiple orthogonal methods","pmids":["22797760"],"is_preprint":false},{"year":2012,"finding":"NaxD, a YdjC superfamily member in Francisella, functions as a deacetylase required for modification of lipid A phosphate with galactosamine; enzymatic assays confirmed deacetylation activity and mass spectrometry identified the lipid A substrate.","method":"Mass spectrometry, enzymatic deacetylase assay, genetic knockout","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus MS substrate identification, consistent with YdjC family deacetylase mechanism; single lab, multiple orthogonal methods","pmids":["22966934"],"is_preprint":false},{"year":2018,"finding":"Human YDJC binds to CDC16 (identified by co-immunoprecipitation); YDJC overexpression promotes ERK activation, keratin 8 phosphorylation and perinuclear reorganization, and cell migration/invasion in A549 lung cancer cells; a deacetylase-dead mutant (YDJCD13A) failed to induce these effects, indicating the catalytic activity is required.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression of wild-type and catalytic mutant (YDJCD13A), ERK phosphorylation assay, migration/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal functional evidence with catalytic mutant control and Co-IP; single lab, multiple readouts but no in vitro reconstitution","pmids":["29796162"],"is_preprint":false},{"year":2019,"finding":"Human YDJC promotes epithelial-mesenchymal transition (EMT) in lung cancer cells through ubiquitination of PP2A; YDJC overexpression reduced PP2A expression and induced its ubiquitination, while the catalytic mutant YDJCD13A could not; CDC16 (a YDJC binding partner) overexpression increased YDJC ubiquitination and suppressed EMT; ERK2 is activated downstream in CDC16-silencing-induced EMT.","method":"Overexpression of wild-type and YDJCD13A mutant, siRNA knockdown of YDJC and CDC16, ubiquitination assay, E-cadherin/N-cadherin immunoblotting, orthotopic mouse model","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — catalytic mutant controls, ubiquitination assays, and in vivo model; single lab, multiple orthogonal methods but no in vitro reconstitution","pmids":["31485224"],"is_preprint":false},{"year":2025,"finding":"YDJC directly deacetylates SREBP2 in CD4+ T cells, suppressing downstream SREBP2 target gene expression (Hmgcr, Hmgcs1, Cyp51) and cholesterol biosynthesis; Ydjc-knockout CD4+ T cells show upregulated SREBP2-mediated cholesterol biosynthesis, enhanced proliferation, and increased Th1 differentiation, leading to exacerbated colitis; pharmacological inhibition of cholesterol biosynthesis (simvastatin, fatostatin, AAV-sh-Srebf2) rescued the Ydjc-/- phenotype.","method":"Ydjc-/- mouse model, integrative transcriptomic/proteomic/metabolomic analyses, direct deacetylation assay of SREBP2, genetic rescue with cholesterol biosynthesis inhibitors (simvastatin, fatostatin, AAV-sh-Srebf2), colitis models","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct substrate deacetylation assay of SREBP2 by YDJC, KO mouse model with specific phenotypic rescue by pathway inhibitors, multiple orthogonal omics methods; single lab but rigorous experimental design","pmids":["41162693"],"is_preprint":false}],"current_model":"Human YDJC is a catalytically active deacetylase (conserved Asp-His-His metal-binding active site defined by crystal structure of a family member) that deacetylates carbohydrate and protein substrates: in CD4+ T cells it directly deacetylates SREBP2 to suppress cholesterol biosynthesis and restrain Th1 differentiation, while in lung cancer cells its deacetylase activity—dependent on CDC16 interaction—drives ERK activation, keratin 8 reorganization, PP2A ubiquitination, and epithelial-mesenchymal transition."},"narrative":{"mechanistic_narrative":"YDJC is a metal-dependent deacetylase whose catalytic architecture is defined by an Asp-His-His metal-binding triad conserved across the YdjC family, originally resolved in the (βα)-barrel fold of the bacterial homolog TTHB029 and shown to resemble peptidoglycan N-acetylglucosamine deacetylase [PMID:18177738]. The enzymatic identity of this family is established by bacterial members that deacetylate carbohydrate and lipid substrates: ChbG deacetylates chitooligosaccharide phosphates, an activity abolished by metal-binding residue substitution [PMID:22797760], and NaxD deacetylates lipid A-linked galactosamine [PMID:22966934]. In human cells YDJC acts as a catalytically active deacetylase with substrate specificity extending to proteins: in CD4+ T cells it directly deacetylates SREBP2 to suppress cholesterol biosynthesis gene expression (Hmgcr, Hmgcs1, Cyp51), restraining T cell proliferation and Th1 differentiation, with Ydjc loss exacerbating colitis through unrestrained SREBP2-driven cholesterol synthesis [PMID:41162693]. In lung cancer cells, YDJC binds CDC16 and, in a manner dependent on its catalytic Asp13 residue, drives ERK activation, keratin 8 phosphorylation and perinuclear reorganization, PP2A ubiquitination, and epithelial-mesenchymal transition, with CDC16 itself promoting YDJC ubiquitination to suppress EMT [PMID:29796162, PMID:31485224].","teleology":[{"year":2008,"claim":"Established the structural and catalytic identity of the YdjC family by resolving the fold and active site, framing human YDJC as a putative metal-dependent deacetylase before any direct human assay existed.","evidence":"X-ray crystallography of T. thermophilus TTHB029 at 2.9 Å with structural comparison to a peptidoglycan deacetylase","pmids":["18177738"],"confidence":"High","gaps":["No human YDJC structure determined","Substrate of the human enzyme not addressed by structure alone"]},{"year":2012,"claim":"Demonstrated that the conserved active site is genuinely catalytic by showing bacterial homologs deacetylate defined substrates, validating the predicted metal-binding triad through loss-of-function mutagenesis.","evidence":"ChbG growth/genetic-epistasis assays on chitooligosaccharides and NaxD enzymatic and mass-spectrometry assays on lipid A in bacteria","pmids":["22797760","22966934"],"confidence":"High","gaps":["Substrates are bacterial carbohydrate/lipid species, not human targets","Does not establish human YDJC activity directly"]},{"year":2018,"claim":"First linked human YDJC catalytic activity to a cellular phenotype, showing a binding partner and that the deacetylase active site is required for promoting oncogenic signaling and motility.","evidence":"Co-IP with CDC16, siRNA, overexpression of wild-type versus YDJCD13A catalytic mutant, ERK phosphorylation and migration/invasion assays in A549 cells","pmids":["29796162"],"confidence":"Medium","gaps":["No in vitro reconstitution of catalysis","Direct enzymatic substrate in this context not identified","CDC16 interaction validated by single Co-IP"]},{"year":2019,"claim":"Extended the lung cancer mechanism by tying YDJC catalytic activity to PP2A ubiquitination and EMT, and positioned CDC16 as a regulator that ubiquitinates YDJC to suppress these effects.","evidence":"Wild-type versus YDJCD13A overexpression, ubiquitination assays, EMT marker immunoblotting, and orthotopic mouse model","pmids":["31485224"],"confidence":"Medium","gaps":["Mechanistic link between deacetylase activity and PP2A ubiquitination not reconstituted","Direct deacetylation substrate not defined in this system"]},{"year":2025,"claim":"Identified a direct protein substrate of human YDJC by showing it deacetylates SREBP2 to restrain cholesterol biosynthesis and Th1 differentiation, providing the strongest direct enzyme-substrate evidence in a mammalian context.","evidence":"Ydjc-/- mouse model, direct SREBP2 deacetylation assay, integrative omics, and genetic/pharmacological cholesterol-pathway rescue in colitis models","pmids":["41162693"],"confidence":"High","gaps":["Acetylation site(s) on SREBP2 and structural basis of recognition not defined","Relationship between the T cell SREBP2 substrate and the lung cancer PP2A/ERK mechanism unresolved"]},{"year":null,"claim":"How a single deacetylase active site discriminates between carbohydrate-derived substrates (bacterial homologs) and protein substrates such as SREBP2, and how its activity intersects with the CDC16-dependent ubiquitination axis, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified biochemical model of human YDJC substrate specificity","No structure of human YDJC bound to a substrate","Tissue-context determinants of T cell versus epithelial function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]}],"complexes":[],"partners":["CDC16","SREBP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A8MPS7","full_name":"Carbohydrate deacetylase","aliases":[],"length_aa":323,"mass_kda":34.5,"function":"Probably catalyzes the deacetylation of acetylated carbohydrates an important step in the degradation of oligosaccharides","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/A8MPS7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YDJC","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/YDJC","total_profiled":1310},"omim":[{"mim_id":"619770","title":"YDJC CHITOOLIGOSACCHARIDE DEACETYLASE HOMOLOG; YDJC","url":"https://www.omim.org/entry/619770"},{"mim_id":"603461","title":"CELL DIVISION CYCLE 16; CDC16","url":"https://www.omim.org/entry/603461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YDJC"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"A8MPS7","domains":[{"cath_id":"3.20.20.370","chopping":"7-302","consensus_level":"medium","plddt":96.181,"start":7,"end":302}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A8MPS7","model_url":"https://alphafold.ebi.ac.uk/files/AF-A8MPS7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A8MPS7-F1-predicted_aligned_error_v6.png","plddt_mean":91.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YDJC","jax_strain_url":"https://www.jax.org/strain/search?query=YDJC"},"sequence":{"accession":"A8MPS7","fasta_url":"https://rest.uniprot.org/uniprotkb/A8MPS7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A8MPS7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A8MPS7"}},"corpus_meta":[{"pmid":"22482804","id":"PMC_22482804","title":"Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22482804","citation_count":277,"is_preprint":false},{"pmid":"22797760","id":"PMC_22797760","title":"The chbG gene of the chitobiose (chb) operon of Escherichia coli encodes a chitooligosaccharide deacetylase.","date":"2012","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/22797760","citation_count":29,"is_preprint":false},{"pmid":"22966934","id":"PMC_22966934","title":"NaxD is a deacetylase required for lipid A modification and Francisella pathogenesis.","date":"2012","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22966934","citation_count":29,"is_preprint":false},{"pmid":"36455308","id":"PMC_36455308","title":"Exploring potential shared genetic influences between rheumatoid arthritis and blood lipid levels.","date":"2022","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/36455308","citation_count":13,"is_preprint":false},{"pmid":"18177738","id":"PMC_18177738","title":"Crystal structure of the YdjC-family protein TTHB029 from Thermus thermophilus HB8: structural relationship with peptidoglycan N-acetylglucosamine deacetylase.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18177738","citation_count":10,"is_preprint":false},{"pmid":"31485224","id":"PMC_31485224","title":"YDJC Induces Epithelial-Mesenchymal Transition via Escaping from Interaction with CDC16 through Ubiquitination of PP2A.","date":"2019","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31485224","citation_count":6,"is_preprint":false},{"pmid":"34279042","id":"PMC_34279042","title":"Variants on the UBE2L3/YDJC Autoimmune Disease Risk Haplotype Increase UBE2L3 Expression by Modulating CCCTC-Binding Factor and YY1 Binding.","date":"2021","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/34279042","citation_count":6,"is_preprint":false},{"pmid":"29796162","id":"PMC_29796162","title":"YdjC chitooligosaccharide deacetylase homolog induces keratin reorganization in lung cancer cells: involvement of interaction between YDJC and CDC16.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29796162","citation_count":4,"is_preprint":false},{"pmid":"41162693","id":"PMC_41162693","title":"YDJC restrains Th1 cell differentiation by blocking SREBP2-mediated cholesterol biosynthesis to alleviate mucosal inflammation in inflammatory bowel disease.","date":"2025","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41162693","citation_count":1,"is_preprint":false},{"pmid":"38844604","id":"PMC_38844604","title":"Unveiling genetic signatures associated with resilience to neonatal diarrhea in lambs through two GWAS approaches.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38844604","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7632,"output_tokens":1799,"usd":0.024941,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8665,"output_tokens":2236,"usd":0.049612,"stage2_stop_reason":"end_turn"},"total_usd":0.074553,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the YdjC-family protein TTHB029 (Thermus thermophilus) was determined at 2.9 Å resolution, revealing a (βα)-barrel fold homodimer with Asp21, His60, and His127 coordinating Mg²⁺ as the probable active site, and structural similarity to peptidoglycan N-acetylglucosamine deacetylase (SpPgdA); the Asp-His-His metal-binding triad is fully conserved across the YdjC family including human YDJC.\",\n      \"method\": \"X-ray crystallography at 2.9 Å resolution with structural comparison\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with active-site identification and cross-family conservation analysis; single study but direct structural determination\",\n      \"pmids\": [\"18177738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The bacterial ydjC homolog chbG encodes a monodeacetylase essential for growth on acetylated chitooligosaccharides (chitobiose, chitotriose); substitution of conserved metal-binding residues abolished activity, validating the predicted active site; deacetylation of chitobiose-6-P and chitotriose-6-P by ChbG is required for their recognition as inducers by the regulatory protein ChbR.\",\n      \"method\": \"Growth assays, loss-of-function mutagenesis of active-site residues, genetic epistasis with chbR mutations\",\n      \"journal\": \"Journal of bacteriology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic activity demonstrated with active-site mutagenesis plus genetic epistasis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22797760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NaxD, a YdjC superfamily member in Francisella, functions as a deacetylase required for modification of lipid A phosphate with galactosamine; enzymatic assays confirmed deacetylation activity and mass spectrometry identified the lipid A substrate.\",\n      \"method\": \"Mass spectrometry, enzymatic deacetylase assay, genetic knockout\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus MS substrate identification, consistent with YdjC family deacetylase mechanism; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22966934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human YDJC binds to CDC16 (identified by co-immunoprecipitation); YDJC overexpression promotes ERK activation, keratin 8 phosphorylation and perinuclear reorganization, and cell migration/invasion in A549 lung cancer cells; a deacetylase-dead mutant (YDJCD13A) failed to induce these effects, indicating the catalytic activity is required.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression of wild-type and catalytic mutant (YDJCD13A), ERK phosphorylation assay, migration/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal functional evidence with catalytic mutant control and Co-IP; single lab, multiple readouts but no in vitro reconstitution\",\n      \"pmids\": [\"29796162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human YDJC promotes epithelial-mesenchymal transition (EMT) in lung cancer cells through ubiquitination of PP2A; YDJC overexpression reduced PP2A expression and induced its ubiquitination, while the catalytic mutant YDJCD13A could not; CDC16 (a YDJC binding partner) overexpression increased YDJC ubiquitination and suppressed EMT; ERK2 is activated downstream in CDC16-silencing-induced EMT.\",\n      \"method\": \"Overexpression of wild-type and YDJCD13A mutant, siRNA knockdown of YDJC and CDC16, ubiquitination assay, E-cadherin/N-cadherin immunoblotting, orthotopic mouse model\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — catalytic mutant controls, ubiquitination assays, and in vivo model; single lab, multiple orthogonal methods but no in vitro reconstitution\",\n      \"pmids\": [\"31485224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YDJC directly deacetylates SREBP2 in CD4+ T cells, suppressing downstream SREBP2 target gene expression (Hmgcr, Hmgcs1, Cyp51) and cholesterol biosynthesis; Ydjc-knockout CD4+ T cells show upregulated SREBP2-mediated cholesterol biosynthesis, enhanced proliferation, and increased Th1 differentiation, leading to exacerbated colitis; pharmacological inhibition of cholesterol biosynthesis (simvastatin, fatostatin, AAV-sh-Srebf2) rescued the Ydjc-/- phenotype.\",\n      \"method\": \"Ydjc-/- mouse model, integrative transcriptomic/proteomic/metabolomic analyses, direct deacetylation assay of SREBP2, genetic rescue with cholesterol biosynthesis inhibitors (simvastatin, fatostatin, AAV-sh-Srebf2), colitis models\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct substrate deacetylation assay of SREBP2 by YDJC, KO mouse model with specific phenotypic rescue by pathway inhibitors, multiple orthogonal omics methods; single lab but rigorous experimental design\",\n      \"pmids\": [\"41162693\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human YDJC is a catalytically active deacetylase (conserved Asp-His-His metal-binding active site defined by crystal structure of a family member) that deacetylates carbohydrate and protein substrates: in CD4+ T cells it directly deacetylates SREBP2 to suppress cholesterol biosynthesis and restrain Th1 differentiation, while in lung cancer cells its deacetylase activity—dependent on CDC16 interaction—drives ERK activation, keratin 8 reorganization, PP2A ubiquitination, and epithelial-mesenchymal transition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YDJC is a metal-dependent deacetylase whose catalytic architecture is defined by an Asp-His-His metal-binding triad conserved across the YdjC family, originally resolved in the (βα)-barrel fold of the bacterial homolog TTHB029 and shown to resemble peptidoglycan N-acetylglucosamine deacetylase [#0]. The enzymatic identity of this family is established by bacterial members that deacetylate carbohydrate and lipid substrates: ChbG deacetylates chitooligosaccharide phosphates, an activity abolished by metal-binding residue substitution [#1], and NaxD deacetylates lipid A-linked galactosamine [#2]. In human cells YDJC acts as a catalytically active deacetylase with substrate specificity extending to proteins: in CD4+ T cells it directly deacetylates SREBP2 to suppress cholesterol biosynthesis gene expression (Hmgcr, Hmgcs1, Cyp51), restraining T cell proliferation and Th1 differentiation, with Ydjc loss exacerbating colitis through unrestrained SREBP2-driven cholesterol synthesis [#5]. In lung cancer cells, YDJC binds CDC16 and, in a manner dependent on its catalytic Asp13 residue, drives ERK activation, keratin 8 phosphorylation and perinuclear reorganization, PP2A ubiquitination, and epithelial-mesenchymal transition, with CDC16 itself promoting YDJC ubiquitination to suppress EMT [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the structural and catalytic identity of the YdjC family by resolving the fold and active site, framing human YDJC as a putative metal-dependent deacetylase before any direct human assay existed.\",\n      \"evidence\": \"X-ray crystallography of T. thermophilus TTHB029 at 2.9 Å with structural comparison to a peptidoglycan deacetylase\",\n      \"pmids\": [\"18177738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No human YDJC structure determined\", \"Substrate of the human enzyme not addressed by structure alone\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that the conserved active site is genuinely catalytic by showing bacterial homologs deacetylate defined substrates, validating the predicted metal-binding triad through loss-of-function mutagenesis.\",\n      \"evidence\": \"ChbG growth/genetic-epistasis assays on chitooligosaccharides and NaxD enzymatic and mass-spectrometry assays on lipid A in bacteria\",\n      \"pmids\": [\"22797760\", \"22966934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates are bacterial carbohydrate/lipid species, not human targets\", \"Does not establish human YDJC activity directly\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"First linked human YDJC catalytic activity to a cellular phenotype, showing a binding partner and that the deacetylase active site is required for promoting oncogenic signaling and motility.\",\n      \"evidence\": \"Co-IP with CDC16, siRNA, overexpression of wild-type versus YDJCD13A catalytic mutant, ERK phosphorylation and migration/invasion assays in A549 cells\",\n      \"pmids\": [\"29796162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of catalysis\", \"Direct enzymatic substrate in this context not identified\", \"CDC16 interaction validated by single Co-IP\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the lung cancer mechanism by tying YDJC catalytic activity to PP2A ubiquitination and EMT, and positioned CDC16 as a regulator that ubiquitinates YDJC to suppress these effects.\",\n      \"evidence\": \"Wild-type versus YDJCD13A overexpression, ubiquitination assays, EMT marker immunoblotting, and orthotopic mouse model\",\n      \"pmids\": [\"31485224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between deacetylase activity and PP2A ubiquitination not reconstituted\", \"Direct deacetylation substrate not defined in this system\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a direct protein substrate of human YDJC by showing it deacetylates SREBP2 to restrain cholesterol biosynthesis and Th1 differentiation, providing the strongest direct enzyme-substrate evidence in a mammalian context.\",\n      \"evidence\": \"Ydjc-/- mouse model, direct SREBP2 deacetylation assay, integrative omics, and genetic/pharmacological cholesterol-pathway rescue in colitis models\",\n      \"pmids\": [\"41162693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation site(s) on SREBP2 and structural basis of recognition not defined\", \"Relationship between the T cell SREBP2 substrate and the lung cancer PP2A/ERK mechanism unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single deacetylase active site discriminates between carbohydrate-derived substrates (bacterial homologs) and protein substrates such as SREBP2, and how its activity intersects with the CDC16-dependent ubiquitination axis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified biochemical model of human YDJC substrate specificity\", \"No structure of human YDJC bound to a substrate\", \"Tissue-context determinants of T cell versus epithelial function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CDC16\", \"SREBP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}