{"gene":"ABHD17C","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2015,"finding":"ABHD17 proteins (including ABHD17C) are novel protein depalmitoylases that catalyze palmitate removal from N-Ras and PSD95; ABHD17C catalytic activity is required for N-Ras depalmitoylation and re-localization from the plasma membrane to internal cellular membranes. APT1/APT2 inhibition (Palmostatin B) does not affect palmitate turnover on N-Ras or PSD95, indicating ABHD17 proteins act as substrate-specific depalmitoylases distinct from APT1/APT2.","method":"Dual pulse-chase strategy comparing palmitate and protein half-lives; activity-based protein profiling (serine hydrolase activity profiling); knockdown/inhibition of APT1/APT2; catalytic mutant analysis; live-cell imaging of N-Ras localization","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (pulse-chase, activity profiling, genetic knockdown, catalytic mutagenesis, subcellular localization), foundational paper establishing the enzymatic activity","pmids":["26701913"],"is_preprint":false},{"year":2023,"finding":"USP35 stabilizes ABHD17C by inhibiting its ubiquitin-proteasome-mediated degradation; USP35 physically interacts with ABHD17C and reduces its ubiquitination. Stabilization of ABHD17C by USP35 activates the PI3K/AKT signaling pathway in hepatocellular carcinoma cells, promoting proliferation and migration.","method":"Co-immunoprecipitation (USP35-ABHD17C interaction); ubiquitination assay; USP35 knockdown with ABHD17C rescue (overexpression); xenograft tumor assay; immunoblotting","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP plus functional rescue experiment and in vivo xenograft, single lab","pmids":["37993419"],"is_preprint":false},{"year":2025,"finding":"ABHD17C (along with ABHD17A and ABHD17B) is the acyl protein thioesterase responsible for deacylation (de-S-acylation) of the innate immune receptor NOD2. Inhibiting ABHD17 isoforms increases plasma membrane localization of NOD2 and enhances NF-κB activation and pro-inflammatory cytokine production in epithelial cells. ABHD17 isoforms thereby act as negative regulators of NOD2 signaling.","method":"RNA interference; small-molecule inhibitors of ABHD17; confocal microscopy; acyl-resin-assisted capture (Acyl-RAC); immunoblotting; cytokine multiplex assays in engineered cell lines","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, pharmacological inhibition, Acyl-RAC biochemistry, microscopy, functional cytokine readout), replicated across preprint and peer-reviewed publication","pmids":["40054525","38187608"],"is_preprint":false},{"year":2025,"finding":"ERK1 (downstream of mutant KRAS) phosphorylates ABHD17C, promoting its depalmitoylase activity toward ALOX15B; ABHD17C-mediated depalmitoylation of ALOX15B causes membrane-to-cytoplasm translocation of ALOX15B and facilitates its proteasome-dependent degradation via the CUL4/DDB1/DCAF10 E3 ligase complex. Disruption of the ABHD17C/ALOX15B interaction by methyl protodioscin (MPD) restores S-palmitoylation and membrane localization of ALOX15B, inducing ferroptosis.","method":"Biochemical phosphorylation assays; depalmitoylation/S-palmitoylation assays; protein interaction studies (ABHD17C/ALOX15B); proteasome inhibition; patient-derived organoid assays; in vivo xenograft assay; small-molecule MPD treatment","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (phosphorylation, palmitoylation, protein interaction, degradation pathway) in single lab with in vivo support, but limited independent replication","pmids":["40569151"],"is_preprint":false},{"year":2025,"finding":"ABHD17C-mediated depalmitoylation of BCL6B at Cys442 impedes importin-α/β-mediated nuclear translocation of BCL6B and drives its ubiquitination-dependent degradation in the cytoplasm. Loss of nuclear BCL6B attenuates transcriptional repression of the anti-phagocytic signal CD24, increases CD24 expression, and enables pancreatic cancer cells to evade macrophage phagocytosis.","method":"Depalmitoylation assays (Cys442 site-specific); importin-α/β interaction assays; ubiquitination assays; transcriptional assays (BCL6B repression of CD24 promoter); CD24 expression analysis; macrophage phagocytosis assay; orthotopic NSG mouse models with ABHD17C-deficient cells","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistically detailed (site-specific depalmitoylation, nuclear transport, transcription, immune evasion) with in vivo support, single lab","pmids":["42154583"],"is_preprint":false},{"year":2025,"finding":"The conserved N-terminal cysteine cluster palmitoylation code that governs ABHD17A plasma membrane targeting and catalytic activity is conserved in ABHD17C; specifically, modification of the middle-region cysteines is critical for plasma membrane targeting and depalmitoylase activity in ABHD17C as well as ABHD17A and ABHD17B.","method":"Alanine-scanning mutagenesis; biochemical acylation assays; confocal microscopy of localization mutants (ABHD17C context verified by sequence analysis and mutagenesis)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis plus biochemical acylation assays and imaging, but finding for ABHD17C is secondary to the primary ABHD17A study in the paper","pmids":["41155484"],"is_preprint":false}],"current_model":"ABHD17C is a serine hydrolase (depalmitoylase) that removes S-palmitoyl groups from specific substrate proteins including N-Ras, PSD95, NOD2, ALOX15B, and BCL6B, thereby controlling their membrane localization, stability, and downstream signaling; its own membrane targeting depends on N-terminal palmitoylation of middle-region cysteines, it is stabilized post-translationally by the deubiquitinase USP35, and its activity is regulated by ERK1-mediated phosphorylation downstream of mutant KRAS."},"narrative":{"mechanistic_narrative":"ABHD17C is a substrate-specific serine hydrolase that acts as a protein depalmitoylase (acyl protein thioesterase), removing S-palmitoyl groups from target proteins to control their membrane association, subcellular distribution, stability, and downstream signaling [PMID:26701913]. Its activity is distinct from APT1/APT2: it catalyzes palmitate removal from N-Ras and PSD95 and drives N-Ras re-localization from the plasma membrane to internal membranes, an activity dependent on its catalytic serine [PMID:26701913]. Across multiple contexts, ABHD17C-mediated depalmitoylation acts as a regulatory switch—de-S-acylation of the innate immune receptor NOD2 reduces its plasma membrane localization and dampens NF-κB-driven inflammatory cytokine output, marking ABHD17C as a negative regulator of NOD2 signaling [PMID:40054525, PMID:38187608]; depalmitoylation of ALOX15B and of BCL6B (at Cys442) triggers their membrane-to-cytoplasm translocation and subsequent ubiquitin-proteasome degradation, the latter via the CUL4/DDB1/DCAF10 ligase complex [PMID:40569151, PMID:42154583]. Its own plasma membrane targeting and catalytic activity require palmitoylation of a conserved middle-region cysteine cluster [PMID:41155484], and the enzyme is post-translationally controlled by USP35-dependent deubiquitination that stabilizes it [PMID:37993419] and by ERK1-mediated phosphorylation downstream of mutant KRAS that promotes its activity [PMID:40569151]. Through these substrate-directed actions, ABHD17C influences tumor cell proliferation, ferroptosis sensitivity, and immune evasion in several cancer models [PMID:37993419, PMID:40569151, PMID:42154583].","teleology":[{"year":2015,"claim":"Established that ABHD17C is a bona fide protein depalmitoylase with substrate specificity distinct from the classical APT1/APT2 thioesterases, answering whether dedicated enzymes beyond APTs control palmitate turnover on signaling proteins.","evidence":"Dual pulse-chase of palmitate vs protein half-life, activity-based serine hydrolase profiling, catalytic mutant and APT1/2 inhibition, live-cell N-Ras imaging","pmids":["26701913"],"confidence":"High","gaps":["Did not define the full substrate repertoire","No structural basis for substrate selection","Mechanism of in vivo regulation not addressed"]},{"year":2023,"claim":"Showed ABHD17C is post-translationally stabilized by the deubiquitinase USP35, linking enzyme abundance to oncogenic PI3K/AKT signaling and defining a layer of upstream control over its protein levels.","evidence":"Reciprocal Co-IP, ubiquitination assay, USP35 knockdown with ABHD17C rescue, and xenograft in hepatocellular carcinoma cells","pmids":["37993419"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Direct depalmitoylase substrates driving PI3K/AKT effect not identified","Whether USP35 acts directly on ABHD17C ubiquitin chains unresolved"]},{"year":2025,"claim":"Identified the innate immune receptor NOD2 as an ABHD17C substrate, establishing ABHD17 isoforms as negative regulators of NOD2 plasma membrane localization and NF-κB inflammatory signaling.","evidence":"RNAi, small-molecule ABHD17 inhibition, Acyl-RAC, confocal microscopy, and cytokine multiplex assays in engineered epithelial cells","pmids":["40054525","38187608"],"confidence":"High","gaps":["Isoform-specific contribution of ABHD17C versus A/B not dissected","De-S-acylated cysteine site on NOD2 not mapped","Physiological/disease relevance in intact tissue not established"]},{"year":2025,"claim":"Connected ABHD17C activity to upstream KRAS-ERK1 signaling and downstream ferroptosis control, showing ERK1 phosphorylation enhances its depalmitoylation of ALOX15B and routes ALOX15B to CUL4/DDB1/DCAF10-dependent degradation.","evidence":"Phosphorylation and palmitoylation assays, ABHD17C/ALOX15B interaction, proteasome inhibition, patient-derived organoids, xenografts, and MPD small-molecule disruption","pmids":["40569151"],"confidence":"Medium","gaps":["Single lab, limited independent replication","Phosphosite(s) on ABHD17C not defined","Generalizability beyond the studied cancer context unclear"]},{"year":2025,"claim":"Demonstrated site-specific depalmitoylation of BCL6B (Cys442) by ABHD17C blocks importin-α/β nuclear import and drives BCL6B degradation, derepressing CD24 to enable cancer immune evasion from macrophage phagocytosis.","evidence":"Site-specific depalmitoylation, importin interaction and ubiquitination assays, CD24 promoter/transcription readouts, phagocytosis assays, and orthotopic NSG mouse models","pmids":["42154583"],"confidence":"Medium","gaps":["Single lab","Coordination with other ABHD17C substrate-directed pathways unknown","Direct enzyme-substrate engagement structure not resolved"]},{"year":2025,"claim":"Defined how ABHD17C achieves its own membrane localization, showing palmitoylation of a conserved N-terminal/middle-region cysteine cluster is required for plasma membrane targeting and catalytic activity.","evidence":"Alanine-scanning mutagenesis, biochemical acylation assays, and confocal imaging of localization mutants","pmids":["41155484"],"confidence":"Medium","gaps":["ABHD17C finding secondary to primary ABHD17A study","Enzyme(s) palmitoylating ABHD17C not identified","Dynamics of self-palmitoylation versus substrate turnover not addressed"]},{"year":null,"claim":"How ABHD17C selects among its diverse substrates (N-Ras, PSD95, NOD2, ALOX15B, BCL6B) and how its phosphorylation, self-palmitoylation, and USP35 stabilization are integrated into a unified regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of substrate recognition","No comprehensive substrate map","Cross-talk between regulatory inputs not reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"complexes":[],"partners":["USP35","NOD2","ALOX15B","BCL6B","NRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PCB6","full_name":"Alpha/beta hydrolase domain-containing protein 17C","aliases":[],"length_aa":329,"mass_kda":35.8,"function":"Hydrolyzes fatty acids from S-acylated cysteine residues in proteins. Has depalmitoylating activity towards NRAS and DLG4/PSD95","subcellular_location":"Recycling endosome membrane; Cell projection, dendritic spine; Postsynaptic density membrane","url":"https://www.uniprot.org/uniprotkb/Q6PCB6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABHD17C","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABHD17C","total_profiled":1310},"omim":[{"mim_id":"617944","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 17C, DEPALMITOYLASE; ABHD17C","url":"https://www.omim.org/entry/617944"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":61.2}],"url":"https://www.proteinatlas.org/search/ABHD17C"},"hgnc":{"alias_symbol":[],"prev_symbol":["FAM108C1"]},"alphafold":{"accession":"Q6PCB6","domains":[{"cath_id":"3.40.50.1820","chopping":"32-46_85-324","consensus_level":"medium","plddt":95.8397,"start":32,"end":324}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PCB6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PCB6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PCB6-F1-predicted_aligned_error_v6.png","plddt_mean":84.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABHD17C","jax_strain_url":"https://www.jax.org/strain/search?query=ABHD17C"},"sequence":{"accession":"Q6PCB6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PCB6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PCB6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PCB6"}},"corpus_meta":[{"pmid":"26701913","id":"PMC_26701913","title":"ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26701913","citation_count":283,"is_preprint":false},{"pmid":"28630138","id":"PMC_28630138","title":"Targeting the Ras palmitoylation/depalmitoylation cycle in cancer.","date":"2017","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/28630138","citation_count":66,"is_preprint":false},{"pmid":"33278272","id":"PMC_33278272","title":"Polygenic Profile of Elite Strength Athletes.","date":"2020","source":"Journal of strength and conditioning research","url":"https://pubmed.ncbi.nlm.nih.gov/33278272","citation_count":42,"is_preprint":false},{"pmid":"37993419","id":"PMC_37993419","title":"USP35 promotes HCC development by stabilizing ABHD17C and activating the PI3K/AKT signaling pathway.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37993419","citation_count":15,"is_preprint":false},{"pmid":"31456818","id":"PMC_31456818","title":"Primary Tumor Site Specificity is Preserved in Patient-Derived Tumor Xenograft Models.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31456818","citation_count":13,"is_preprint":false},{"pmid":"40569151","id":"PMC_40569151","title":"KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40569151","citation_count":7,"is_preprint":false},{"pmid":"40054525","id":"PMC_40054525","title":"Attenuating ABHD17 Isoforms Augments the S-acylation and Function of NOD2 and a Subset of Crohn's Disease-associated NOD2 Variants.","date":"2025","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40054525","citation_count":7,"is_preprint":false},{"pmid":"38187608","id":"PMC_38187608","title":"Attenuating ABHD17 isoforms augments the S-acylation and function of NOD2 and a subset of Crohn's disease-associated NOD2 variants.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38187608","citation_count":6,"is_preprint":false},{"pmid":"38396844","id":"PMC_38396844","title":"Differential Expression of MicroRNA MiR-145 and MiR-155 Downstream Targets in Oral Cancers Exhibiting Limited Chemotherapy Resistance.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38396844","citation_count":5,"is_preprint":false},{"pmid":"40582697","id":"PMC_40582697","title":"Single-Cell Sequencing Reveals the Palmitoylation Landscape in Lung Adenocarcinoma and Identifies ABHD17C as a Novel Biomarker.","date":"2025","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40582697","citation_count":2,"is_preprint":false},{"pmid":"39262472","id":"PMC_39262472","title":"Long non-coding RNA MIR4435-2HG promotes pancreatic cancer progression by regulating ABHD17C through sponging miR-128-3p.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39262472","citation_count":2,"is_preprint":false},{"pmid":"41155484","id":"PMC_41155484","title":"Palmitoylation Code and Endosomal Sorting Regulate ABHD17A Plasma Membrane Targeting and Activity.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41155484","citation_count":1,"is_preprint":false},{"pmid":"42154583","id":"PMC_42154583","title":"ABHD17C-Mediated S-Depalmitoylation of BCL6B Enhances CD24 Transcription to Resist Macrophage Phagocytosis in Pancreatic Cancer.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42154583","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9094,"output_tokens":2029,"usd":0.028858,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8954,"output_tokens":2778,"usd":0.05711,"stage2_stop_reason":"end_turn"},"total_usd":0.085968,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"ABHD17 proteins (including ABHD17C) are novel protein depalmitoylases that catalyze palmitate removal from N-Ras and PSD95; ABHD17C catalytic activity is required for N-Ras depalmitoylation and re-localization from the plasma membrane to internal cellular membranes. APT1/APT2 inhibition (Palmostatin B) does not affect palmitate turnover on N-Ras or PSD95, indicating ABHD17 proteins act as substrate-specific depalmitoylases distinct from APT1/APT2.\",\n      \"method\": \"Dual pulse-chase strategy comparing palmitate and protein half-lives; activity-based protein profiling (serine hydrolase activity profiling); knockdown/inhibition of APT1/APT2; catalytic mutant analysis; live-cell imaging of N-Ras localization\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (pulse-chase, activity profiling, genetic knockdown, catalytic mutagenesis, subcellular localization), foundational paper establishing the enzymatic activity\",\n      \"pmids\": [\"26701913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP35 stabilizes ABHD17C by inhibiting its ubiquitin-proteasome-mediated degradation; USP35 physically interacts with ABHD17C and reduces its ubiquitination. Stabilization of ABHD17C by USP35 activates the PI3K/AKT signaling pathway in hepatocellular carcinoma cells, promoting proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation (USP35-ABHD17C interaction); ubiquitination assay; USP35 knockdown with ABHD17C rescue (overexpression); xenograft tumor assay; immunoblotting\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP plus functional rescue experiment and in vivo xenograft, single lab\",\n      \"pmids\": [\"37993419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17C (along with ABHD17A and ABHD17B) is the acyl protein thioesterase responsible for deacylation (de-S-acylation) of the innate immune receptor NOD2. Inhibiting ABHD17 isoforms increases plasma membrane localization of NOD2 and enhances NF-κB activation and pro-inflammatory cytokine production in epithelial cells. ABHD17 isoforms thereby act as negative regulators of NOD2 signaling.\",\n      \"method\": \"RNA interference; small-molecule inhibitors of ABHD17; confocal microscopy; acyl-resin-assisted capture (Acyl-RAC); immunoblotting; cytokine multiplex assays in engineered cell lines\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, pharmacological inhibition, Acyl-RAC biochemistry, microscopy, functional cytokine readout), replicated across preprint and peer-reviewed publication\",\n      \"pmids\": [\"40054525\", \"38187608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ERK1 (downstream of mutant KRAS) phosphorylates ABHD17C, promoting its depalmitoylase activity toward ALOX15B; ABHD17C-mediated depalmitoylation of ALOX15B causes membrane-to-cytoplasm translocation of ALOX15B and facilitates its proteasome-dependent degradation via the CUL4/DDB1/DCAF10 E3 ligase complex. Disruption of the ABHD17C/ALOX15B interaction by methyl protodioscin (MPD) restores S-palmitoylation and membrane localization of ALOX15B, inducing ferroptosis.\",\n      \"method\": \"Biochemical phosphorylation assays; depalmitoylation/S-palmitoylation assays; protein interaction studies (ABHD17C/ALOX15B); proteasome inhibition; patient-derived organoid assays; in vivo xenograft assay; small-molecule MPD treatment\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (phosphorylation, palmitoylation, protein interaction, degradation pathway) in single lab with in vivo support, but limited independent replication\",\n      \"pmids\": [\"40569151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17C-mediated depalmitoylation of BCL6B at Cys442 impedes importin-α/β-mediated nuclear translocation of BCL6B and drives its ubiquitination-dependent degradation in the cytoplasm. Loss of nuclear BCL6B attenuates transcriptional repression of the anti-phagocytic signal CD24, increases CD24 expression, and enables pancreatic cancer cells to evade macrophage phagocytosis.\",\n      \"method\": \"Depalmitoylation assays (Cys442 site-specific); importin-α/β interaction assays; ubiquitination assays; transcriptional assays (BCL6B repression of CD24 promoter); CD24 expression analysis; macrophage phagocytosis assay; orthotopic NSG mouse models with ABHD17C-deficient cells\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistically detailed (site-specific depalmitoylation, nuclear transport, transcription, immune evasion) with in vivo support, single lab\",\n      \"pmids\": [\"42154583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The conserved N-terminal cysteine cluster palmitoylation code that governs ABHD17A plasma membrane targeting and catalytic activity is conserved in ABHD17C; specifically, modification of the middle-region cysteines is critical for plasma membrane targeting and depalmitoylase activity in ABHD17C as well as ABHD17A and ABHD17B.\",\n      \"method\": \"Alanine-scanning mutagenesis; biochemical acylation assays; confocal microscopy of localization mutants (ABHD17C context verified by sequence analysis and mutagenesis)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis plus biochemical acylation assays and imaging, but finding for ABHD17C is secondary to the primary ABHD17A study in the paper\",\n      \"pmids\": [\"41155484\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABHD17C is a serine hydrolase (depalmitoylase) that removes S-palmitoyl groups from specific substrate proteins including N-Ras, PSD95, NOD2, ALOX15B, and BCL6B, thereby controlling their membrane localization, stability, and downstream signaling; its own membrane targeting depends on N-terminal palmitoylation of middle-region cysteines, it is stabilized post-translationally by the deubiquitinase USP35, and its activity is regulated by ERK1-mediated phosphorylation downstream of mutant KRAS.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABHD17C is a substrate-specific serine hydrolase that acts as a protein depalmitoylase (acyl protein thioesterase), removing S-palmitoyl groups from target proteins to control their membrane association, subcellular distribution, stability, and downstream signaling [#0]. Its activity is distinct from APT1/APT2: it catalyzes palmitate removal from N-Ras and PSD95 and drives N-Ras re-localization from the plasma membrane to internal membranes, an activity dependent on its catalytic serine [#0]. Across multiple contexts, ABHD17C-mediated depalmitoylation acts as a regulatory switch—de-S-acylation of the innate immune receptor NOD2 reduces its plasma membrane localization and dampens NF-\\u03baB-driven inflammatory cytokine output, marking ABHD17C as a negative regulator of NOD2 signaling [#2]; depalmitoylation of ALOX15B and of BCL6B (at Cys442) triggers their membrane-to-cytoplasm translocation and subsequent ubiquitin-proteasome degradation, the latter via the CUL4/DDB1/DCAF10 ligase complex [#3, #4]. Its own plasma membrane targeting and catalytic activity require palmitoylation of a conserved middle-region cysteine cluster [#5], and the enzyme is post-translationally controlled by USP35-dependent deubiquitination that stabilizes it [#1] and by ERK1-mediated phosphorylation downstream of mutant KRAS that promotes its activity [#3]. Through these substrate-directed actions, ABHD17C influences tumor cell proliferation, ferroptosis sensitivity, and immune evasion in several cancer models [#1, #3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that ABHD17C is a bona fide protein depalmitoylase with substrate specificity distinct from the classical APT1/APT2 thioesterases, answering whether dedicated enzymes beyond APTs control palmitate turnover on signaling proteins.\",\n      \"evidence\": \"Dual pulse-chase of palmitate vs protein half-life, activity-based serine hydrolase profiling, catalytic mutant and APT1/2 inhibition, live-cell N-Ras imaging\",\n      \"pmids\": [\"26701913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full substrate repertoire\", \"No structural basis for substrate selection\", \"Mechanism of in vivo regulation not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ABHD17C is post-translationally stabilized by the deubiquitinase USP35, linking enzyme abundance to oncogenic PI3K/AKT signaling and defining a layer of upstream control over its protein levels.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, USP35 knockdown with ABHD17C rescue, and xenograft in hepatocellular carcinoma cells\",\n      \"pmids\": [\"37993419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Direct depalmitoylase substrates driving PI3K/AKT effect not identified\", \"Whether USP35 acts directly on ABHD17C ubiquitin chains unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the innate immune receptor NOD2 as an ABHD17C substrate, establishing ABHD17 isoforms as negative regulators of NOD2 plasma membrane localization and NF-\\u03baB inflammatory signaling.\",\n      \"evidence\": \"RNAi, small-molecule ABHD17 inhibition, Acyl-RAC, confocal microscopy, and cytokine multiplex assays in engineered epithelial cells\",\n      \"pmids\": [\"40054525\", \"38187608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific contribution of ABHD17C versus A/B not dissected\", \"De-S-acylated cysteine site on NOD2 not mapped\", \"Physiological/disease relevance in intact tissue not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ABHD17C activity to upstream KRAS-ERK1 signaling and downstream ferroptosis control, showing ERK1 phosphorylation enhances its depalmitoylation of ALOX15B and routes ALOX15B to CUL4/DDB1/DCAF10-dependent degradation.\",\n      \"evidence\": \"Phosphorylation and palmitoylation assays, ABHD17C/ALOX15B interaction, proteasome inhibition, patient-derived organoids, xenografts, and MPD small-molecule disruption\",\n      \"pmids\": [\"40569151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, limited independent replication\", \"Phosphosite(s) on ABHD17C not defined\", \"Generalizability beyond the studied cancer context unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated site-specific depalmitoylation of BCL6B (Cys442) by ABHD17C blocks importin-\\u03b1/\\u03b2 nuclear import and drives BCL6B degradation, derepressing CD24 to enable cancer immune evasion from macrophage phagocytosis.\",\n      \"evidence\": \"Site-specific depalmitoylation, importin interaction and ubiquitination assays, CD24 promoter/transcription readouts, phagocytosis assays, and orthotopic NSG mouse models\",\n      \"pmids\": [\"42154583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Coordination with other ABHD17C substrate-directed pathways unknown\", \"Direct enzyme-substrate engagement structure not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined how ABHD17C achieves its own membrane localization, showing palmitoylation of a conserved N-terminal/middle-region cysteine cluster is required for plasma membrane targeting and catalytic activity.\",\n      \"evidence\": \"Alanine-scanning mutagenesis, biochemical acylation assays, and confocal imaging of localization mutants\",\n      \"pmids\": [\"41155484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ABHD17C finding secondary to primary ABHD17A study\", \"Enzyme(s) palmitoylating ABHD17C not identified\", \"Dynamics of self-palmitoylation versus substrate turnover not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ABHD17C selects among its diverse substrates (N-Ras, PSD95, NOD2, ALOX15B, BCL6B) and how its phosphorylation, self-palmitoylation, and USP35 stabilization are integrated into a unified regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"No comprehensive substrate map\", \"Cross-talk between regulatory inputs not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"USP35\", \"NOD2\", \"ALOX15B\", \"BCL6B\", \"NRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}