{"gene":"ABHD17C","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2015,"finding":"ABHD17 proteins (including ABHD17C) are novel serine hydrolase depalmitoylases that catalyze palmitate removal from N-Ras and PSD95; catalytic activity of ABHD17C is required for N-Ras depalmitoylation and re-localization to internal cellular membranes.","method":"Dual pulse-chase palmitate/protein half-life assay, activity-based protein profiling, knockdown, overexpression with subcellular localization readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (activity profiling, pulse-chase, localization assays), foundational paper with 273 citations","pmids":["26701913"],"is_preprint":false},{"year":2023,"finding":"USP35 interacts with ABHD17C and stabilizes it by inhibiting ubiquitin-proteasome-mediated degradation; ABHD17C overexpression rescues defects caused by USP35 knockdown in HCC cells, and this axis activates PI3K/AKT signaling.","method":"Co-IP, ubiquitination assay, knockdown/overexpression with proliferation, cell cycle, apoptosis, and xenograft readouts","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional rescue, single lab","pmids":["37993419"],"is_preprint":false},{"year":2025,"finding":"ABHD17C acts as a depalmitoylase for ALOX15B downstream of KRAS-mutant/ERK1 signaling; ERK1-elicited phosphorylation of ABHD17C promotes its depalmitoylation of ALOX15B, causing membrane-to-cytoplasm translocation and subsequent proteasome-dependent degradation of ALOX15B via the CUL4/DDB1/DCAF10 E3 ligase complex.","method":"Biochemical fractionation, phosphorylation assays, Co-IP with E3 ligase components, organoid and xenograft models, pharmacological disruption of ABHD17C/ALOX15B interaction","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including Co-IP, fractionation, in vivo models; single lab","pmids":["40569151"],"is_preprint":false},{"year":2025,"finding":"ABHD17A, ABHD17B, and ABHD17C are the acyl protein thioesterases responsible for deacylation (depalmitoylation) of NOD2; inhibiting ABHD17 isoforms increases plasma membrane localization of NOD2, enhancing NF-κB activation and pro-inflammatory cytokine production.","method":"RNA interference, small-molecule inhibitors, confocal microscopy, acyl-resin-assisted capture (acyl-RAC), immunoblotting, cytokine multiplex assay","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNAi, chemical inhibition, acyl-RAC, functional signaling readouts), replicated in peer-reviewed and preprint forms","pmids":["40054525","38187608"],"is_preprint":false},{"year":2025,"finding":"The middle-region cysteine residues (C14, C15) of the conserved N-terminal cysteine cluster are critical for plasma membrane targeting and catalytic activity of ABHD17 family members, and this requirement is conserved in ABHD17C; YXXØ-dependent endosomal sorting is required for plasma membrane delivery of ABHD17A, with the mechanism conserved in ABHD17C.","method":"Alanine scanning mutagenesis, subcellular localization imaging, biochemical acylation assays, code-restricted mutants","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 — mutagenesis plus biochemical assays, conservation demonstrated in ABHD17C specifically; single lab","pmids":["41155484"],"is_preprint":false},{"year":2024,"finding":"miR-128-3p directly targets ABHD17C mRNA; the lncRNA MIR4435-2HG sponges miR-128-3p to upregulate ABHD17C expression, promoting pancreatic cancer cell proliferation, migration, and invasion.","method":"Dual-luciferase reporter assay, RNA pull-down, RIP assay, qRT-PCR, knockdown with cellular phenotype readouts, xenograft","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding validated by luciferase reporter, RNA pull-down, and RIP; single lab","pmids":["39262472"],"is_preprint":false}],"current_model":"ABHD17C is a serine hydrolase depalmitoylase that removes S-palmitoylation from multiple substrates including N-Ras, PSD95, NOD2, and ALOX15B, thereby controlling their membrane localization and downstream signaling; its stability is regulated by USP35-mediated deubiquitination, its activity is modulated by ERK1-dependent phosphorylation downstream of oncogenic KRAS, and its own plasma membrane targeting depends on N-terminal palmitoylation and YXXØ-dependent endosomal sorting conserved across ABHD17 family members."},"narrative":{"teleology":[{"year":2015,"claim":"The discovery that ABHD17 family members, including ABHD17C, are bona fide serine hydrolase depalmitoylases established a new enzymatic mechanism for Ras and PSD95 depalmitoylation, resolving the long-standing question of which thioesterases catalyze palmitate turnover on these substrates.","evidence":"Activity-based protein profiling, dual pulse-chase palmitate/protein half-life assays, and subcellular localization of N-Ras upon ABHD17C overexpression in mammalian cells","pmids":["26701913"],"confidence":"High","gaps":["Full substrate scope of ABHD17C beyond N-Ras and PSD95 was unknown","Regulatory mechanisms controlling ABHD17C catalytic activity were uncharacterized","Structural basis for substrate recognition had not been determined"]},{"year":2023,"claim":"Identification of USP35 as a deubiquitinase that stabilizes ABHD17C protein levels revealed a post-translational layer of regulation, connecting ABHD17C abundance to ubiquitin-proteasome control and downstream PI3K/AKT signaling in hepatocellular carcinoma.","evidence":"Reciprocal Co-IP, ubiquitination assays, knockdown/overexpression rescue in HCC cell lines and xenografts","pmids":["37993419"],"confidence":"Medium","gaps":["The specific ubiquitin ligase targeting ABHD17C for degradation was not identified","Whether USP35-ABHD17C regulation operates in non-HCC contexts is unknown","The link to PI3K/AKT was shown functionally but the direct mechanistic intermediary (specific depalmitoylation substrate) was not defined"]},{"year":2024,"claim":"Demonstration that miR-128-3p directly targets ABHD17C mRNA, sponged by lncRNA MIR4435-2HG, identified a transcriptional/post-transcriptional regulatory axis controlling ABHD17C expression in pancreatic cancer.","evidence":"Dual-luciferase reporter, RNA pull-down, RIP assay, knockdown with proliferation/migration readouts, xenograft","pmids":["39262472"],"confidence":"Medium","gaps":["Whether the oncogenic phenotype is mediated through specific ABHD17C depalmitoylase substrates was not tested","Generalizability beyond pancreatic cancer cell lines is unconfirmed"]},{"year":2025,"claim":"Expanding the substrate repertoire, ABHD17C was shown to depalmitoylate NOD2, establishing that ABHD17 family thioesterases regulate innate immune receptor membrane localization and NF-κB-driven cytokine production.","evidence":"RNAi, ABHD17 small-molecule inhibitors, acyl-RAC, confocal microscopy, and cytokine multiplex assays in macrophage-like cells","pmids":["40054525"],"confidence":"High","gaps":["Individual contributions of ABHD17A/B/C to NOD2 depalmitoylation were not fully resolved due to shared inhibitor targeting","In vivo relevance to inflammatory bowel disease or other NOD2-linked pathologies was not tested"]},{"year":2025,"claim":"ERK1-dependent phosphorylation of ABHD17C was found to stimulate its depalmitoylation of ALOX15B, connecting oncogenic KRAS signaling to lipid-metabolic enzyme turnover via membrane-to-cytoplasm translocation and subsequent CUL4/DDB1/DCAF10-mediated proteasomal degradation.","evidence":"Phosphorylation assays, biochemical fractionation, Co-IP with E3 ligase components, organoid and xenograft models, pharmacological disruption of ABHD17C–ALOX15B interaction","pmids":["40569151"],"confidence":"Medium","gaps":["The specific phosphorylation site(s) on ABHD17C and their structural impact on catalysis are not resolved","Whether ERK1-mediated regulation generalizes to other ABHD17C substrates is unknown"]},{"year":2025,"claim":"Mutagenesis of the conserved N-terminal cysteine cluster revealed that middle-region cysteines C14/C15 are critical for ABHD17C palmitoylation, plasma membrane targeting, and catalytic activity, while YXXφ motif–dependent endosomal sorting is required for membrane delivery.","evidence":"Alanine scanning mutagenesis, subcellular localization imaging, and biochemical acylation assays with ABHD17 family members including ABHD17C","pmids":["41155484"],"confidence":"Medium","gaps":["The palmitoyltransferase(s) responsible for ABHD17C acylation are not identified","No structural model of ABHD17C explains how palmitoylation and the YXXφ motif cooperate in trafficking"]},{"year":null,"claim":"A high-resolution structure of ABHD17C, a comprehensive substrate inventory beyond N-Ras/PSD95/NOD2/ALOX15B, and the integration of its multiple regulatory inputs (phosphorylation, ubiquitination, palmitoylation, miRNA) into a unified signaling model remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of any ABHD17 family member","Systematic palmitoyl-proteomics to define full ABHD17C substrate scope not performed","Relative contributions of ABHD17A/B/C to shared substrates in physiological settings are poorly delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4]}],"complexes":[],"partners":["USP35","ALOX15B","NRAS","NOD2","DLG4"],"other_free_text":[]},"mechanistic_narrative":"ABHD17C is a serine hydrolase that functions as a protein depalmitoylase, removing S-palmitoylation from substrates including N-Ras, PSD95, NOD2, and ALOX15B to control their membrane association and downstream signaling [PMID:26701913, PMID:40054525, PMID:40569151]. Its own plasma membrane targeting depends on palmitoylation of conserved N-terminal cysteine residues (particularly C14 and C15) and YXXφ-dependent endosomal sorting [PMID:41155484]. ABHD17C activity is positively regulated by ERK1-dependent phosphorylation downstream of oncogenic KRAS, linking its depalmitoylase function to KRAS-driven signaling in cancer [PMID:40569151], and its protein stability is maintained by USP35-mediated deubiquitination, which promotes PI3K/AKT pathway activation [PMID:37993419]."},"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":273,"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":64,"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":41,"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":6,"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":6,"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":"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":"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":0,"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":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7807,"output_tokens":1565,"usd":0.023448},"stage2":{"model":"claude-opus-4-6","input_tokens":4818,"output_tokens":2174,"usd":0.11766},"total_usd":0.141108,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"ABHD17 proteins (including ABHD17C) are novel serine hydrolase depalmitoylases that catalyze palmitate removal from N-Ras and PSD95; catalytic activity of ABHD17C is required for N-Ras depalmitoylation and re-localization to internal cellular membranes.\",\n      \"method\": \"Dual pulse-chase palmitate/protein half-life assay, activity-based protein profiling, knockdown, overexpression with subcellular localization readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (activity profiling, pulse-chase, localization assays), foundational paper with 273 citations\",\n      \"pmids\": [\"26701913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP35 interacts with ABHD17C and stabilizes it by inhibiting ubiquitin-proteasome-mediated degradation; ABHD17C overexpression rescues defects caused by USP35 knockdown in HCC cells, and this axis activates PI3K/AKT signaling.\",\n      \"method\": \"Co-IP, ubiquitination assay, knockdown/overexpression with proliferation, cell cycle, apoptosis, and xenograft readouts\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional rescue, single lab\",\n      \"pmids\": [\"37993419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17C acts as a depalmitoylase for ALOX15B downstream of KRAS-mutant/ERK1 signaling; ERK1-elicited phosphorylation of ABHD17C promotes its depalmitoylation of ALOX15B, causing membrane-to-cytoplasm translocation and subsequent proteasome-dependent degradation of ALOX15B via the CUL4/DDB1/DCAF10 E3 ligase complex.\",\n      \"method\": \"Biochemical fractionation, phosphorylation assays, Co-IP with E3 ligase components, organoid and xenograft models, pharmacological disruption of ABHD17C/ALOX15B interaction\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, fractionation, in vivo models; single lab\",\n      \"pmids\": [\"40569151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17A, ABHD17B, and ABHD17C are the acyl protein thioesterases responsible for deacylation (depalmitoylation) of NOD2; inhibiting ABHD17 isoforms increases plasma membrane localization of NOD2, enhancing NF-κB activation and pro-inflammatory cytokine production.\",\n      \"method\": \"RNA interference, small-molecule inhibitors, confocal microscopy, acyl-resin-assisted capture (acyl-RAC), immunoblotting, cytokine multiplex assay\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi, chemical inhibition, acyl-RAC, functional signaling readouts), replicated in peer-reviewed and preprint forms\",\n      \"pmids\": [\"40054525\", \"38187608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The middle-region cysteine residues (C14, C15) of the conserved N-terminal cysteine cluster are critical for plasma membrane targeting and catalytic activity of ABHD17 family members, and this requirement is conserved in ABHD17C; YXXØ-dependent endosomal sorting is required for plasma membrane delivery of ABHD17A, with the mechanism conserved in ABHD17C.\",\n      \"method\": \"Alanine scanning mutagenesis, subcellular localization imaging, biochemical acylation assays, code-restricted mutants\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis plus biochemical assays, conservation demonstrated in ABHD17C specifically; single lab\",\n      \"pmids\": [\"41155484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-128-3p directly targets ABHD17C mRNA; the lncRNA MIR4435-2HG sponges miR-128-3p to upregulate ABHD17C expression, promoting pancreatic cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Dual-luciferase reporter assay, RNA pull-down, RIP assay, qRT-PCR, knockdown with cellular phenotype readouts, xenograft\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding validated by luciferase reporter, RNA pull-down, and RIP; single lab\",\n      \"pmids\": [\"39262472\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABHD17C is a serine hydrolase depalmitoylase that removes S-palmitoylation from multiple substrates including N-Ras, PSD95, NOD2, and ALOX15B, thereby controlling their membrane localization and downstream signaling; its stability is regulated by USP35-mediated deubiquitination, its activity is modulated by ERK1-dependent phosphorylation downstream of oncogenic KRAS, and its own plasma membrane targeting depends on N-terminal palmitoylation and YXXØ-dependent endosomal sorting conserved across ABHD17 family members.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ABHD17C is a serine hydrolase that functions as a protein depalmitoylase, removing S-palmitoylation from substrates including N-Ras, PSD95, NOD2, and ALOX15B to control their membrane association and downstream signaling [PMID:26701913, PMID:40054525, PMID:40569151]. Its own plasma membrane targeting depends on palmitoylation of conserved N-terminal cysteine residues (particularly C14 and C15) and YXXφ-dependent endosomal sorting [PMID:41155484]. ABHD17C activity is positively regulated by ERK1-dependent phosphorylation downstream of oncogenic KRAS, linking its depalmitoylase function to KRAS-driven signaling in cancer [PMID:40569151], and its protein stability is maintained by USP35-mediated deubiquitination, which promotes PI3K/AKT pathway activation [PMID:37993419].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"The discovery that ABHD17 family members, including ABHD17C, are bona fide serine hydrolase depalmitoylases established a new enzymatic mechanism for Ras and PSD95 depalmitoylation, resolving the long-standing question of which thioesterases catalyze palmitate turnover on these substrates.\",\n      \"evidence\": \"Activity-based protein profiling, dual pulse-chase palmitate/protein half-life assays, and subcellular localization of N-Ras upon ABHD17C overexpression in mammalian cells\",\n      \"pmids\": [\"26701913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full substrate scope of ABHD17C beyond N-Ras and PSD95 was unknown\",\n        \"Regulatory mechanisms controlling ABHD17C catalytic activity were uncharacterized\",\n        \"Structural basis for substrate recognition had not been determined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of USP35 as a deubiquitinase that stabilizes ABHD17C protein levels revealed a post-translational layer of regulation, connecting ABHD17C abundance to ubiquitin-proteasome control and downstream PI3K/AKT signaling in hepatocellular carcinoma.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, knockdown/overexpression rescue in HCC cell lines and xenografts\",\n      \"pmids\": [\"37993419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific ubiquitin ligase targeting ABHD17C for degradation was not identified\",\n        \"Whether USP35-ABHD17C regulation operates in non-HCC contexts is unknown\",\n        \"The link to PI3K/AKT was shown functionally but the direct mechanistic intermediary (specific depalmitoylation substrate) was not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that miR-128-3p directly targets ABHD17C mRNA, sponged by lncRNA MIR4435-2HG, identified a transcriptional/post-transcriptional regulatory axis controlling ABHD17C expression in pancreatic cancer.\",\n      \"evidence\": \"Dual-luciferase reporter, RNA pull-down, RIP assay, knockdown with proliferation/migration readouts, xenograft\",\n      \"pmids\": [\"39262472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the oncogenic phenotype is mediated through specific ABHD17C depalmitoylase substrates was not tested\",\n        \"Generalizability beyond pancreatic cancer cell lines is unconfirmed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanding the substrate repertoire, ABHD17C was shown to depalmitoylate NOD2, establishing that ABHD17 family thioesterases regulate innate immune receptor membrane localization and NF-κB-driven cytokine production.\",\n      \"evidence\": \"RNAi, ABHD17 small-molecule inhibitors, acyl-RAC, confocal microscopy, and cytokine multiplex assays in macrophage-like cells\",\n      \"pmids\": [\"40054525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of ABHD17A/B/C to NOD2 depalmitoylation were not fully resolved due to shared inhibitor targeting\",\n        \"In vivo relevance to inflammatory bowel disease or other NOD2-linked pathologies was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ERK1-dependent phosphorylation of ABHD17C was found to stimulate its depalmitoylation of ALOX15B, connecting oncogenic KRAS signaling to lipid-metabolic enzyme turnover via membrane-to-cytoplasm translocation and subsequent CUL4/DDB1/DCAF10-mediated proteasomal degradation.\",\n      \"evidence\": \"Phosphorylation assays, biochemical fractionation, Co-IP with E3 ligase components, organoid and xenograft models, pharmacological disruption of ABHD17C–ALOX15B interaction\",\n      \"pmids\": [\"40569151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific phosphorylation site(s) on ABHD17C and their structural impact on catalysis are not resolved\",\n        \"Whether ERK1-mediated regulation generalizes to other ABHD17C substrates is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mutagenesis of the conserved N-terminal cysteine cluster revealed that middle-region cysteines C14/C15 are critical for ABHD17C palmitoylation, plasma membrane targeting, and catalytic activity, while YXXφ motif–dependent endosomal sorting is required for membrane delivery.\",\n      \"evidence\": \"Alanine scanning mutagenesis, subcellular localization imaging, and biochemical acylation assays with ABHD17 family members including ABHD17C\",\n      \"pmids\": [\"41155484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The palmitoyltransferase(s) responsible for ABHD17C acylation are not identified\",\n        \"No structural model of ABHD17C explains how palmitoylation and the YXXφ motif cooperate in trafficking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of ABHD17C, a comprehensive substrate inventory beyond N-Ras/PSD95/NOD2/ALOX15B, and the integration of its multiple regulatory inputs (phosphorylation, ubiquitination, palmitoylation, miRNA) into a unified signaling model remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of any ABHD17 family member\",\n        \"Systematic palmitoyl-proteomics to define full ABHD17C substrate scope not performed\",\n        \"Relative contributions of ABHD17A/B/C to shared substrates in physiological settings are poorly delineated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"USP35\",\n      \"ALOX15B\",\n      \"NRAS\",\n      \"NOD2\",\n      \"DLG4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}