{"gene":"ABHD17A","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2015,"finding":"ABHD17A (and ABHD17B/C) are novel protein depalmitoylases that catalyze palmitate removal from N-Ras and PSD-95; catalytic activity of ABHD17 is required for N-Ras depalmitoylation and re-localization to internal cellular membranes, and ABHD17 proteins were identified as serine hydrolase targets of Palmostatin B via activity profiling.","method":"Dual pulse-chase palmitate/protein half-life comparison, activity-based protein profiling, knockdown/inhibition with subcellular localization readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (activity profiling, pulse-chase, KD with localization readout), foundational discovery replicated by independent lab","pmids":["26701913"],"is_preprint":false},{"year":2016,"finding":"ABHD17A, 17B, and 17C are the physiological depalmitoylating enzymes for PSD-95 in neurons; ABHD17 members localize to recycling endosomes, dendritic plasma membrane, and synaptic fraction, and their expression reduces PSD-95 palmitoylation and synaptic clustering of PSD-95 and AMPA receptors; inhibition of ABHD17 expression dramatically delays PSD-95 depalmitoylation kinetics.","method":"Serine hydrolase screen in heterologous cells, acyl-PEGyl exchange gel shift (APEGS) assay, neuron expression/knockdown with synaptic clustering readout, subcellular fractionation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (APEGS quantitative assay, localization, KD with functional synaptic readout), independent replication of ABHD17 depalmitoylase activity","pmids":["27307232"],"is_preprint":false},{"year":2017,"finding":"ABHD17A-C depalmitoylating enzymes control shuttling of MAP6 between membranes and microtubules and are required for MAP6 retention in axons; dynamic palmitoylation mediated by ABHD17 family governs MAP6 targeting to the proximal axon for microtubule stabilization.","method":"Live imaging, overexpression/knockdown with localization and microtubule-binding readouts in cultured neurons and in situ","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and localization readout, single lab","pmids":["28521134"],"is_preprint":false},{"year":2019,"finding":"ABHD17A acts as a depalmitoylase for TEAD transcription factors; depalmitoylation of TEAD by ABHD17A (and APT2) leads to TEAD instability and proteasomal degradation via E3 ubiquitin ligase CHIP, as part of cell-density-dependent regulation of TEAD activity downstream of Nf2/Merlin.","method":"Overexpression/knockdown with palmitoylation and protein stability assays, epistasis with CHIP E3 ligase","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD with defined palmitoylation and stability readout, pathway placement established, single lab","pmids":["31043565"],"is_preprint":false},{"year":2020,"finding":"ABHD17A deacylates BK channel splice variants in a site-specific manner: it deacylates the stress-regulated exon (STREX) domain of BK channels to inhibit channel activity, but has no effect on the S0-S1 domain (which is deacylated by Lypla1), demonstrating substrate-domain specificity within the same polytopic transmembrane protein.","method":"Overexpression/KD with electrophysiology (channel activity), acylation assays, domain-specific mutagenesis comparison","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional readout (channel activity) combined with site-specific acylation assays, single lab","pmids":["32913120"],"is_preprint":false},{"year":2021,"finding":"ABHD17A depalmitoylase reverses palmitoylation of CNAβ1 (a calcineurin isoform), which controls CNAβ1 localization at the plasma membrane and Golgi; palmitoylation by ABHD17A substrates governs CNAβ1 targeting to the PI4KA complex.","method":"Overexpression/KD with subcellular fractionation, palmitoylation assay, interactome by MS, hydrogen-deuterium exchange","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (HDX, MS interactome, localization, KD), single lab","pmids":["34663815"],"is_preprint":false},{"year":2023,"finding":"ABHD17A depalmitoylates NLRP3 at its LRR domain, counteracting ZDHHC5-mediated palmitoylation; a human disease-associated NLRP3 mutation is associated with defective ABHD17A binding and hyper-palmitoylation, linking ABHD17A to inflammasome assembly regulation.","method":"Co-IP, palmitoylation assay, overexpression/KD with inflammasome activation readouts (caspase-1, IL-1β, GSDMD), mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, palmitoylation assay, KD with functional readouts, mutagenesis, in vivo mouse model), rigorous mechanistic study","pmids":["38092000"],"is_preprint":false},{"year":2024,"finding":"ABHD17A is the depalmitoylating enzyme for Rap2b at C176/C177; ABHD17A depalmitoylation of Rap2b alters its plasma membrane localization and inhibits CRC cell migration and invasion; PI3K phosphorylates ABHD17A to modulate its activity in an EGFR/PI3K-dependent manner.","method":"Overexpression/KD with palmitoylation assay, confocal localization, migration/invasion assays, PI3K inhibitor treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple functional readouts combined with palmitoylation and localization assays, single lab","pmids":["39277583"],"is_preprint":false},{"year":2024,"finding":"ABHD17A depalmitoylates SCAP, opposing ZDHHC3-mediated palmitoylation of SCAP at C264, thereby regulating SCAP stability and cholesterol biosynthesis in hepatocellular carcinoma.","method":"Overexpression/KD with palmitoylation assay (acyl-RAC), cholesterol biosynthesis assays, ubiquitination assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — palmitoylation assay combined with functional metabolic readouts, single lab","pmids":["39522165"],"is_preprint":false},{"year":2025,"finding":"ABHD17A (and ABHD17B/C) are the acyl-protein thioesterases responsible for NOD2 deacylation; inhibiting ABHD17 increases plasma membrane localization of NOD2 and enhances NOD2-dependent NF-κB activation and pro-inflammatory cytokine production; ABHD17 inhibition also restores function to a subset of poorly acylated Crohn's disease-associated NOD2 variants.","method":"RNA interference, small-molecule inhibitors, confocal microscopy, acyl-resin-assisted capture, immunoblotting, cytokine multiplex assays","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods with functional and localization readouts, single lab","pmids":["40054525"],"is_preprint":false},{"year":2025,"finding":"ABHD17A physically interacts with IFITM1 and indirectly increases IFITM1 S-palmitoylation by downregulating ABHD16A (another depalmitoylase), thereby enhancing IFITM1 antiviral activity; this reveals an unconventional pro-palmitoylation role for ABHD17A via suppression of a competing depalmitoylase.","method":"Co-IP, palmitoylation assay, overexpression/KD with antiviral activity readout, candidate enzyme screen","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional readouts plus candidate enzyme screen, single lab","pmids":["40723864"],"is_preprint":false},{"year":2025,"finding":"ABHD17A's own N-terminal cysteine cluster (palmitoylation code) governs its intracellular distribution and plasma membrane targeting; middle-region cysteines (C14, C15) are critical for PM targeting and catalytic activity; a YXXØ endosomal sorting motif (proximal L115) is required for PM delivery via the trans-Golgi network; disruption of this motif redirects ABHD17A to autophagosomes.","method":"Alanine scanning mutagenesis, code-restricted mutants, confocal localization, biochemical acylation assays, autophagosome marker co-localization","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — systematic mutagenesis combined with localization and biochemical assays, single lab","pmids":["41155484"],"is_preprint":false},{"year":2026,"finding":"ABHD17A is a deacylating enzyme that regulates the dynamic S-acylation cycle of GSDMA; ABHD17A deacylation of GSDMA modulates GSDMA membrane anchoring and oligomerization relevant to pyroptosis.","method":"Acylation assays, overexpression/KD with pyroptosis readouts, membrane fractionation","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional readout (pyroptosis) combined with acylation assay, single lab","pmids":["41972293"],"is_preprint":false},{"year":2026,"finding":"ABHD17A depalmitoylates METTL3 at C376, opposing ZDHHC24-mediated palmitoylation; S-palmitoylation promotes METTL3 condensate formation near ribosomes and suppresses chaperone-mediated autophagy to stabilize METTL3; a small molecule (Isoborneol) that disrupts METTL3-ABHD17A interaction enhances METTL3 S-palmitoylation and alleviates osteoarthritis in mice.","method":"Palmitoylation assay, Co-IP, AI-guided small-molecule screen, condensate imaging, autophagy assays, OA mouse model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, palmitoylation assay, condensate imaging, in vivo model), single lab","pmids":["41719123"],"is_preprint":false}],"current_model":"ABHD17A is a membrane-anchored serine hydrolase (depalmitoylase) that removes palmitate from a broad range of substrates including N-Ras, PSD-95, MAP6, TEAD, BK channels, CNAβ1, NLRP3, Rap2b, SCAP, NOD2, GSDMA, and METTL3 in a substrate- and site-specific manner; its own plasma membrane targeting and catalytic activity are governed by an N-terminal palmitoylation code and YXXØ-dependent endosomal sorting, and its depalmitoylase activity regulates substrate membrane localization, signaling, and stability across neuronal, immune, and oncogenic contexts."},"narrative":{"teleology":[{"year":2015,"claim":"The identity of physiological protein depalmitoylases beyond APT1/APT2 was unknown; activity-based profiling of Palmostatin B targets and pulse-chase assays established ABHD17A (and 17B/C) as bona fide serine hydrolases that catalyze palmitate removal from N-Ras and PSD-95, founding a new depalmitoylase family.","evidence":"Activity-based protein profiling, dual pulse-chase palmitate/protein half-life assays, knockdown with subcellular localization readout in heterologous cells","pmids":["26701913"],"confidence":"High","gaps":["Endogenous substrate scope beyond N-Ras and PSD-95 not yet defined","Structural basis for substrate recognition unknown","Relative contribution of ABHD17A vs. 17B/17C not resolved"]},{"year":2016,"claim":"Whether ABHD17 family members are the physiological depalmitoylases for PSD-95 in neurons was unresolved; a serine hydrolase screen combined with quantitative APEGS assays in neurons demonstrated that ABHD17 proteins control PSD-95 depalmitoylation kinetics and regulate synaptic clustering of PSD-95 and AMPA receptors.","evidence":"Serine hydrolase screen, APEGS gel-shift assay, neuron expression/knockdown with synaptic clustering readout, subcellular fractionation","pmids":["27307232"],"confidence":"High","gaps":["Whether ABHD17A selectively acts on PSD-95 versus other postsynaptic palmitoylated proteins not tested","In vivo behavioral consequences of ABHD17 loss not assessed"]},{"year":2017,"claim":"How MAP6 (a neuronal microtubule-stabilizing protein) shuttles between membranes and microtubules was unclear; ABHD17A-C were shown to depalmitoylate MAP6, controlling its release from membranes and retention in the proximal axon for microtubule stabilization.","evidence":"Live imaging, overexpression/knockdown with localization and microtubule-binding readouts in cultured neurons","pmids":["28521134"],"confidence":"Medium","gaps":["Direct biochemical reconstitution of ABHD17A–MAP6 depalmitoylation not performed","Whether ABHD17A acts at a specific palmitoylation site on MAP6 not determined"]},{"year":2019,"claim":"The mechanism linking cell-density sensing to TEAD transcription factor turnover was unknown; ABHD17A was identified as a TEAD depalmitoylase whose activity triggers CHIP E3 ligase-mediated ubiquitination and proteasomal degradation, placing ABHD17A in the Hippo/Nf2 signaling axis.","evidence":"Overexpression/knockdown with palmitoylation and protein stability assays, epistasis with CHIP E3 ligase","pmids":["31043565"],"confidence":"Medium","gaps":["Endogenous ABHD17A regulation downstream of Nf2/Merlin not fully mapped","Relative contribution of ABHD17A versus APT2 in TEAD depalmitoylation not quantified"]},{"year":2020,"claim":"Whether depalmitoylases display site-specificity on polytopic membrane proteins was untested; ABHD17A was shown to deacylate the STREX domain but not the S0-S1 domain of BK channels (the latter being a Lypla1 substrate), establishing substrate-domain selectivity within a single target.","evidence":"Overexpression/knockdown with electrophysiology, acylation assays, domain-specific mutagenesis","pmids":["32913120"],"confidence":"Medium","gaps":["Structural determinants of ABHD17A domain selectivity unknown","In vivo consequences for BK channel physiology not assessed"]},{"year":2021,"claim":"The role of dynamic palmitoylation in calcineurin localization was unexplored; ABHD17A was found to depalmitoylate CNAβ1, controlling its distribution between the plasma membrane and Golgi and its association with the PI4KA complex.","evidence":"Overexpression/knockdown with subcellular fractionation, palmitoylation assay, MS interactome, hydrogen-deuterium exchange","pmids":["34663815"],"confidence":"Medium","gaps":["Whether ABHD17A-mediated depalmitoylation of CNAβ1 affects downstream calcineurin signaling not directly tested"]},{"year":2023,"claim":"How palmitoylation of NLRP3 is reversed and whether this contributes to inflammasome regulation was unknown; ABHD17A was identified as the depalmitoylase opposing ZDHHC5-mediated NLRP3 palmitoylation at the LRR domain, and a human NLRP3 disease mutation was shown to impair ABHD17A binding, causing hyper-palmitoylation and aberrant inflammasome activation.","evidence":"Co-IP, palmitoylation assay, overexpression/knockdown with inflammasome readouts (caspase-1, IL-1β, GSDMD), mutagenesis, in vivo mouse model","pmids":["38092000"],"confidence":"High","gaps":["Whether ABHD17A loss alone is sufficient for autoinflammatory disease in vivo not shown","Precise structural interface of ABHD17A–NLRP3 interaction not determined"]},{"year":2024,"claim":"How ABHD17A activity is regulated by upstream signaling was unknown; PI3K was shown to phosphorylate ABHD17A downstream of EGFR, modulating its depalmitoylase activity toward Rap2b and thereby controlling CRC cell migration and invasion.","evidence":"Overexpression/knockdown with palmitoylation assay, confocal localization, migration/invasion assays, PI3K inhibitor treatment","pmids":["39277583"],"confidence":"Medium","gaps":["Phosphorylation site(s) on ABHD17A not mapped","Whether PI3K-mediated regulation extends to other ABHD17A substrates not tested"]},{"year":2024,"claim":"Whether ABHD17A participates in metabolic lipid regulation was unexplored; ABHD17A was found to depalmitoylate SCAP at C264, opposing ZDHHC3, to regulate SCAP stability and cholesterol biosynthesis in hepatocellular carcinoma cells.","evidence":"Overexpression/knockdown with acyl-RAC palmitoylation assay, cholesterol biosynthesis assays, ubiquitination assay","pmids":["39522165"],"confidence":"Medium","gaps":["In vivo relevance of ABHD17A-SCAP axis for cholesterol homeostasis not confirmed"]},{"year":2025,"claim":"The deacylase controlling NOD2 palmitoylation dynamics and its relevance to Crohn's disease variants was unknown; ABHD17A (with 17B/C) was identified as the NOD2 deacylating enzyme, and ABHD17 inhibition restored plasma membrane localization and NF-κB signaling to poorly acylated Crohn's disease-associated NOD2 variants.","evidence":"RNAi, small-molecule inhibitors, confocal microscopy, acyl-resin-assisted capture, cytokine multiplex assays","pmids":["40054525"],"confidence":"Medium","gaps":["Whether ABHD17 inhibition has therapeutic benefit in Crohn's disease models in vivo not tested","Individual contributions of ABHD17A/B/C to NOD2 deacylation not resolved"]},{"year":2025,"claim":"How ABHD17A's own membrane targeting is determined was incompletely understood; systematic mutagenesis revealed that middle-region N-terminal cysteines (C14/C15) are critical for plasma membrane delivery and catalytic competence, and a YXXφ motif directs ABHD17A through the trans-Golgi network—disruption reroutes ABHD17A to autophagosomes.","evidence":"Alanine scanning mutagenesis, code-restricted mutants, confocal localization, biochemical acylation assays, autophagosome marker co-localization","pmids":["41155484"],"confidence":"Medium","gaps":["Functional consequences of autophagosomal mis-targeting on substrate depalmitoylation not quantified","Whether ABHD17A degradation via autophagy is physiologically regulated unknown"]},{"year":2025,"claim":"An unconventional role beyond direct depalmitoylation was revealed: ABHD17A interacts with IFITM1 and indirectly increases IFITM1 S-palmitoylation by downregulating the competing depalmitoylase ABHD16A, enhancing IFITM1 antiviral activity.","evidence":"Co-IP, palmitoylation assay, overexpression/knockdown with antiviral activity readout, candidate enzyme screen","pmids":["40723864"],"confidence":"Medium","gaps":["Mechanism by which ABHD17A downregulates ABHD16A not elucidated","Whether this indirect pro-palmitoylation role extends to other substrates unknown"]},{"year":2026,"claim":"Whether ABHD17A deacylates gasdermin family members and contributes to pyroptosis regulation was untested; ABHD17A was shown to deacylate GSDMA, modulating its membrane anchoring and oligomerization relevant to pyroptotic pore formation.","evidence":"Acylation assays, overexpression/knockdown with pyroptosis readouts, membrane fractionation","pmids":["41972293"],"confidence":"Medium","gaps":["Whether ABHD17A regulates other gasdermin family members not assessed","Reconstitution with purified components not performed"]},{"year":2026,"claim":"The palmitoylation cycle of METTL3 and its functional consequences were unknown; ABHD17A was identified as the depalmitoylase opposing ZDHHC24-mediated METTL3 palmitoylation at C376, controlling METTL3 condensate formation near ribosomes and its degradation via chaperone-mediated autophagy, with therapeutic relevance in osteoarthritis.","evidence":"Palmitoylation assay, Co-IP, AI-guided small-molecule screen, condensate imaging, autophagy assays, OA mouse model","pmids":["41719123"],"confidence":"Medium","gaps":["Whether disruption of ABHD17A–METTL3 interaction affects m6A modification broadly not determined","Specificity of the Isoborneol small molecule for METTL3–ABHD17A not fully characterized"]},{"year":null,"claim":"No crystal or cryo-EM structure of ABHD17A exists, leaving the structural basis for its broad yet site-specific substrate recognition unresolved; the relative non-redundant contributions of ABHD17A versus 17B and 17C across tissues remain poorly defined; and whether ABHD17A loss causes a discrete in vivo phenotype or disease in animal models has not been established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ABHD17A","Genetic knockout phenotype in animal models not reported","Quantitative substrate preference hierarchy not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,3,4,5,6,7,8,9,12,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,6,8,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,6,8,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8]}],"complexes":[],"partners":["PSD95","NRAS","NLRP3","TEAD1","SCAP","NOD2","METTL3","IFITM1"],"other_free_text":[]},"mechanistic_narrative":"ABHD17A is a membrane-anchored serine hydrolase that functions as a broad-specificity protein depalmitoylase (acyl-protein thioesterase), removing S-palmitoyl groups from substrates including N-Ras, PSD-95, MAP6, TEAD transcription factors, BK channels, CNAβ1, NLRP3, Rap2b, SCAP, NOD2, GSDMA, and METTL3, thereby controlling their membrane association, stability, and signaling output [PMID:26701913, PMID:27307232, PMID:38092000, PMID:39277583, PMID:41972293]. Depalmitoylation by ABHD17A governs diverse cellular processes: it regulates PSD-95 synaptic clustering and AMPA receptor retention in neurons, NLRP3 inflammasome assembly in innate immunity, Hippo-pathway TEAD stability via CHIP-mediated proteasomal degradation, SCAP-dependent cholesterol biosynthesis, and METTL3 condensate formation near ribosomes [PMID:27307232, PMID:38092000, PMID:31043565, PMID:39522165, PMID:41719123]. ABHD17A's own plasma membrane targeting depends on an N-terminal palmitoylation code—particularly middle-region cysteines C14/C15—and a YXXφ endosomal sorting motif that directs trafficking through the trans-Golgi network; disruption of this motif redirects ABHD17A to autophagosomes [PMID:41155484]. ABHD17A activity is itself modulated by PI3K-dependent phosphorylation downstream of EGFR signaling [PMID:39277583]."},"prefetch_data":{"uniprot":{"accession":"Q96GS6","full_name":"Alpha/beta hydrolase domain-containing protein 17A","aliases":[],"length_aa":310,"mass_kda":34.0,"function":"Hydrolyzes fatty acids from S-acylated cysteine residues in proteins (PubMed:26701913). Has depalmitoylating activity towards NRAS (PubMed:26701913). Has depalmitoylating activity towards DLG4/PSD95 (PubMed:26701913). May have depalmitoylating activity towards MAP6 (By similarity)","subcellular_location":"Cell membrane; Endosome membrane; Cell projection, dendritic spine; Postsynaptic density membrane","url":"https://www.uniprot.org/uniprotkb/Q96GS6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABHD17A","classification":"Not Classified","n_dependent_lines":196,"n_total_lines":1208,"dependency_fraction":0.16225165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABHD17A","total_profiled":1310},"omim":[{"mim_id":"617944","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 17C, DEPALMITOYLASE; ABHD17C","url":"https://www.omim.org/entry/617944"},{"mim_id":"617943","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 17B, DEPALMITOYLASE; ABHD17B","url":"https://www.omim.org/entry/617943"},{"mim_id":"617942","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 17A, DEPALMITOYLASE; ABHD17A","url":"https://www.omim.org/entry/617942"},{"mim_id":"164790","title":"NRAS PROTOONCOGENE, GTPase; NRAS","url":"https://www.omim.org/entry/164790"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":203.3}],"url":"https://www.proteinatlas.org/search/ABHD17A"},"hgnc":{"alias_symbol":["MGC5244"],"prev_symbol":["C19orf27","FAM108A1"]},"alphafold":{"accession":"Q96GS6","domains":[{"cath_id":"3.40.50.1820","chopping":"65-307","consensus_level":"medium","plddt":96.7056,"start":65,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GS6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GS6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GS6-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABHD17A","jax_strain_url":"https://www.jax.org/strain/search?query=ABHD17A"},"sequence":{"accession":"Q96GS6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96GS6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96GS6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GS6"}},"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":"27307232","id":"PMC_27307232","title":"Identification of PSD-95 Depalmitoylating Enzymes.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27307232","citation_count":189,"is_preprint":false},{"pmid":"36018061","id":"PMC_36018061","title":"Protein palmitoylation in cancer: molecular functions and therapeutic potential.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36018061","citation_count":143,"is_preprint":false},{"pmid":"38092000","id":"PMC_38092000","title":"ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38092000","citation_count":110,"is_preprint":false},{"pmid":"28521134","id":"PMC_28521134","title":"Dynamic Palmitoylation Targets MAP6 to the Axon to Promote Microtubule Stabilization during Neuronal Polarization.","date":"2017","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/28521134","citation_count":91,"is_preprint":false},{"pmid":"28485685","id":"PMC_28485685","title":"Protein palmitoylation: Palmitoyltransferases and their specificity.","date":"2017","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/28485685","citation_count":78,"is_preprint":false},{"pmid":"31043565","id":"PMC_31043565","title":"Cell contact and Nf2/Merlin-dependent regulation of TEAD palmitoylation and activity.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31043565","citation_count":77,"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":"34663815","id":"PMC_34663815","title":"Palmitoylation targets the calcineurin phosphatase to the phosphatidylinositol 4-kinase complex at the plasma membrane.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34663815","citation_count":40,"is_preprint":false},{"pmid":"39522165","id":"PMC_39522165","title":"ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma.","date":"2024","source":"Cell 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palmitate/protein half-life comparison, activity-based protein profiling, knockdown/inhibition with subcellular localization readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (activity profiling, pulse-chase, KD with localization readout), foundational discovery replicated by independent lab\",\n      \"pmids\": [\"26701913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ABHD17A, 17B, and 17C are the physiological depalmitoylating enzymes for PSD-95 in neurons; ABHD17 members localize to recycling endosomes, dendritic plasma membrane, and synaptic fraction, and their expression reduces PSD-95 palmitoylation and synaptic clustering of PSD-95 and AMPA receptors; inhibition of ABHD17 expression dramatically delays PSD-95 depalmitoylation kinetics.\",\n      \"method\": \"Serine hydrolase screen in heterologous cells, acyl-PEGyl exchange gel shift (APEGS) assay, neuron expression/knockdown with synaptic clustering readout, subcellular fractionation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (APEGS quantitative assay, localization, KD with functional synaptic readout), independent replication of ABHD17 depalmitoylase activity\",\n      \"pmids\": [\"27307232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ABHD17A-C depalmitoylating enzymes control shuttling of MAP6 between membranes and microtubules and are required for MAP6 retention in axons; dynamic palmitoylation mediated by ABHD17 family governs MAP6 targeting to the proximal axon for microtubule stabilization.\",\n      \"method\": \"Live imaging, overexpression/knockdown with localization and microtubule-binding readouts in cultured neurons and in situ\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and localization readout, single lab\",\n      \"pmids\": [\"28521134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ABHD17A acts as a depalmitoylase for TEAD transcription factors; depalmitoylation of TEAD by ABHD17A (and APT2) leads to TEAD instability and proteasomal degradation via E3 ubiquitin ligase CHIP, as part of cell-density-dependent regulation of TEAD activity downstream of Nf2/Merlin.\",\n      \"method\": \"Overexpression/knockdown with palmitoylation and protein stability assays, epistasis with CHIP E3 ligase\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD with defined palmitoylation and stability readout, pathway placement established, single lab\",\n      \"pmids\": [\"31043565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ABHD17A deacylates BK channel splice variants in a site-specific manner: it deacylates the stress-regulated exon (STREX) domain of BK channels to inhibit channel activity, but has no effect on the S0-S1 domain (which is deacylated by Lypla1), demonstrating substrate-domain specificity within the same polytopic transmembrane protein.\",\n      \"method\": \"Overexpression/KD with electrophysiology (channel activity), acylation assays, domain-specific mutagenesis comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional readout (channel activity) combined with site-specific acylation assays, single lab\",\n      \"pmids\": [\"32913120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ABHD17A depalmitoylase reverses palmitoylation of CNAβ1 (a calcineurin isoform), which controls CNAβ1 localization at the plasma membrane and Golgi; palmitoylation by ABHD17A substrates governs CNAβ1 targeting to the PI4KA complex.\",\n      \"method\": \"Overexpression/KD with subcellular fractionation, palmitoylation assay, interactome by MS, hydrogen-deuterium exchange\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (HDX, MS interactome, localization, KD), single lab\",\n      \"pmids\": [\"34663815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ABHD17A depalmitoylates NLRP3 at its LRR domain, counteracting ZDHHC5-mediated palmitoylation; a human disease-associated NLRP3 mutation is associated with defective ABHD17A binding and hyper-palmitoylation, linking ABHD17A to inflammasome assembly regulation.\",\n      \"method\": \"Co-IP, palmitoylation assay, overexpression/KD with inflammasome activation readouts (caspase-1, IL-1β, GSDMD), mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, palmitoylation assay, KD with functional readouts, mutagenesis, in vivo mouse model), rigorous mechanistic study\",\n      \"pmids\": [\"38092000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ABHD17A is the depalmitoylating enzyme for Rap2b at C176/C177; ABHD17A depalmitoylation of Rap2b alters its plasma membrane localization and inhibits CRC cell migration and invasion; PI3K phosphorylates ABHD17A to modulate its activity in an EGFR/PI3K-dependent manner.\",\n      \"method\": \"Overexpression/KD with palmitoylation assay, confocal localization, migration/invasion assays, PI3K inhibitor treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional readouts combined with palmitoylation and localization assays, single lab\",\n      \"pmids\": [\"39277583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ABHD17A depalmitoylates SCAP, opposing ZDHHC3-mediated palmitoylation of SCAP at C264, thereby regulating SCAP stability and cholesterol biosynthesis in hepatocellular carcinoma.\",\n      \"method\": \"Overexpression/KD with palmitoylation assay (acyl-RAC), cholesterol biosynthesis assays, ubiquitination assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — palmitoylation assay combined with functional metabolic readouts, single lab\",\n      \"pmids\": [\"39522165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17A (and ABHD17B/C) are the acyl-protein thioesterases responsible for NOD2 deacylation; inhibiting ABHD17 increases plasma membrane localization of NOD2 and enhances NOD2-dependent NF-κB activation and pro-inflammatory cytokine production; ABHD17 inhibition also restores function to a subset of poorly acylated Crohn's disease-associated NOD2 variants.\",\n      \"method\": \"RNA interference, small-molecule inhibitors, confocal microscopy, acyl-resin-assisted capture, immunoblotting, cytokine multiplex assays\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with functional and localization readouts, single lab\",\n      \"pmids\": [\"40054525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17A physically interacts with IFITM1 and indirectly increases IFITM1 S-palmitoylation by downregulating ABHD16A (another depalmitoylase), thereby enhancing IFITM1 antiviral activity; this reveals an unconventional pro-palmitoylation role for ABHD17A via suppression of a competing depalmitoylase.\",\n      \"method\": \"Co-IP, palmitoylation assay, overexpression/KD with antiviral activity readout, candidate enzyme screen\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional readouts plus candidate enzyme screen, single lab\",\n      \"pmids\": [\"40723864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD17A's own N-terminal cysteine cluster (palmitoylation code) governs its intracellular distribution and plasma membrane targeting; middle-region cysteines (C14, C15) are critical for PM targeting and catalytic activity; a YXXØ endosomal sorting motif (proximal L115) is required for PM delivery via the trans-Golgi network; disruption of this motif redirects ABHD17A to autophagosomes.\",\n      \"method\": \"Alanine scanning mutagenesis, code-restricted mutants, confocal localization, biochemical acylation assays, autophagosome marker co-localization\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic mutagenesis combined with localization and biochemical assays, single lab\",\n      \"pmids\": [\"41155484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ABHD17A is a deacylating enzyme that regulates the dynamic S-acylation cycle of GSDMA; ABHD17A deacylation of GSDMA modulates GSDMA membrane anchoring and oligomerization relevant to pyroptosis.\",\n      \"method\": \"Acylation assays, overexpression/KD with pyroptosis readouts, membrane fractionation\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional readout (pyroptosis) combined with acylation assay, single lab\",\n      \"pmids\": [\"41972293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ABHD17A depalmitoylates METTL3 at C376, opposing ZDHHC24-mediated palmitoylation; S-palmitoylation promotes METTL3 condensate formation near ribosomes and suppresses chaperone-mediated autophagy to stabilize METTL3; a small molecule (Isoborneol) that disrupts METTL3-ABHD17A interaction enhances METTL3 S-palmitoylation and alleviates osteoarthritis in mice.\",\n      \"method\": \"Palmitoylation assay, Co-IP, AI-guided small-molecule screen, condensate imaging, autophagy assays, OA mouse model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, palmitoylation assay, condensate imaging, in vivo model), single lab\",\n      \"pmids\": [\"41719123\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABHD17A is a membrane-anchored serine hydrolase (depalmitoylase) that removes palmitate from a broad range of substrates including N-Ras, PSD-95, MAP6, TEAD, BK channels, CNAβ1, NLRP3, Rap2b, SCAP, NOD2, GSDMA, and METTL3 in a substrate- and site-specific manner; its own plasma membrane targeting and catalytic activity are governed by an N-terminal palmitoylation code and YXXØ-dependent endosomal sorting, and its depalmitoylase activity regulates substrate membrane localization, signaling, and stability across neuronal, immune, and oncogenic contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ABHD17A is a membrane-anchored serine hydrolase that functions as a broad-specificity protein depalmitoylase (acyl-protein thioesterase), removing S-palmitoyl groups from substrates including N-Ras, PSD-95, MAP6, TEAD transcription factors, BK channels, CNAβ1, NLRP3, Rap2b, SCAP, NOD2, GSDMA, and METTL3, thereby controlling their membrane association, stability, and signaling output [PMID:26701913, PMID:27307232, PMID:38092000, PMID:39277583, PMID:41972293]. Depalmitoylation by ABHD17A governs diverse cellular processes: it regulates PSD-95 synaptic clustering and AMPA receptor retention in neurons, NLRP3 inflammasome assembly in innate immunity, Hippo-pathway TEAD stability via CHIP-mediated proteasomal degradation, SCAP-dependent cholesterol biosynthesis, and METTL3 condensate formation near ribosomes [PMID:27307232, PMID:38092000, PMID:31043565, PMID:39522165, PMID:41719123]. ABHD17A's own plasma membrane targeting depends on an N-terminal palmitoylation code—particularly middle-region cysteines C14/C15—and a YXXφ endosomal sorting motif that directs trafficking through the trans-Golgi network; disruption of this motif redirects ABHD17A to autophagosomes [PMID:41155484]. ABHD17A activity is itself modulated by PI3K-dependent phosphorylation downstream of EGFR signaling [PMID:39277583].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"The identity of physiological protein depalmitoylases beyond APT1/APT2 was unknown; activity-based profiling of Palmostatin B targets and pulse-chase assays established ABHD17A (and 17B/C) as bona fide serine hydrolases that catalyze palmitate removal from N-Ras and PSD-95, founding a new depalmitoylase family.\",\n      \"evidence\": \"Activity-based protein profiling, dual pulse-chase palmitate/protein half-life assays, knockdown with subcellular localization readout in heterologous cells\",\n      \"pmids\": [\"26701913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrate scope beyond N-Ras and PSD-95 not yet defined\", \"Structural basis for substrate recognition unknown\", \"Relative contribution of ABHD17A vs. 17B/17C not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether ABHD17 family members are the physiological depalmitoylases for PSD-95 in neurons was unresolved; a serine hydrolase screen combined with quantitative APEGS assays in neurons demonstrated that ABHD17 proteins control PSD-95 depalmitoylation kinetics and regulate synaptic clustering of PSD-95 and AMPA receptors.\",\n      \"evidence\": \"Serine hydrolase screen, APEGS gel-shift assay, neuron expression/knockdown with synaptic clustering readout, subcellular fractionation\",\n      \"pmids\": [\"27307232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ABHD17A selectively acts on PSD-95 versus other postsynaptic palmitoylated proteins not tested\", \"In vivo behavioral consequences of ABHD17 loss not assessed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"How MAP6 (a neuronal microtubule-stabilizing protein) shuttles between membranes and microtubules was unclear; ABHD17A-C were shown to depalmitoylate MAP6, controlling its release from membranes and retention in the proximal axon for microtubule stabilization.\",\n      \"evidence\": \"Live imaging, overexpression/knockdown with localization and microtubule-binding readouts in cultured neurons\",\n      \"pmids\": [\"28521134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical reconstitution of ABHD17A–MAP6 depalmitoylation not performed\", \"Whether ABHD17A acts at a specific palmitoylation site on MAP6 not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The mechanism linking cell-density sensing to TEAD transcription factor turnover was unknown; ABHD17A was identified as a TEAD depalmitoylase whose activity triggers CHIP E3 ligase-mediated ubiquitination and proteasomal degradation, placing ABHD17A in the Hippo/Nf2 signaling axis.\",\n      \"evidence\": \"Overexpression/knockdown with palmitoylation and protein stability assays, epistasis with CHIP E3 ligase\",\n      \"pmids\": [\"31043565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous ABHD17A regulation downstream of Nf2/Merlin not fully mapped\", \"Relative contribution of ABHD17A versus APT2 in TEAD depalmitoylation not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether depalmitoylases display site-specificity on polytopic membrane proteins was untested; ABHD17A was shown to deacylate the STREX domain but not the S0-S1 domain of BK channels (the latter being a Lypla1 substrate), establishing substrate-domain selectivity within a single target.\",\n      \"evidence\": \"Overexpression/knockdown with electrophysiology, acylation assays, domain-specific mutagenesis\",\n      \"pmids\": [\"32913120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural determinants of ABHD17A domain selectivity unknown\", \"In vivo consequences for BK channel physiology not assessed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The role of dynamic palmitoylation in calcineurin localization was unexplored; ABHD17A was found to depalmitoylate CNAβ1, controlling its distribution between the plasma membrane and Golgi and its association with the PI4KA complex.\",\n      \"evidence\": \"Overexpression/knockdown with subcellular fractionation, palmitoylation assay, MS interactome, hydrogen-deuterium exchange\",\n      \"pmids\": [\"34663815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ABHD17A-mediated depalmitoylation of CNAβ1 affects downstream calcineurin signaling not directly tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How palmitoylation of NLRP3 is reversed and whether this contributes to inflammasome regulation was unknown; ABHD17A was identified as the depalmitoylase opposing ZDHHC5-mediated NLRP3 palmitoylation at the LRR domain, and a human NLRP3 disease mutation was shown to impair ABHD17A binding, causing hyper-palmitoylation and aberrant inflammasome activation.\",\n      \"evidence\": \"Co-IP, palmitoylation assay, overexpression/knockdown with inflammasome readouts (caspase-1, IL-1β, GSDMD), mutagenesis, in vivo mouse model\",\n      \"pmids\": [\"38092000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ABHD17A loss alone is sufficient for autoinflammatory disease in vivo not shown\", \"Precise structural interface of ABHD17A–NLRP3 interaction not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How ABHD17A activity is regulated by upstream signaling was unknown; PI3K was shown to phosphorylate ABHD17A downstream of EGFR, modulating its depalmitoylase activity toward Rap2b and thereby controlling CRC cell migration and invasion.\",\n      \"evidence\": \"Overexpression/knockdown with palmitoylation assay, confocal localization, migration/invasion assays, PI3K inhibitor treatment\",\n      \"pmids\": [\"39277583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site(s) on ABHD17A not mapped\", \"Whether PI3K-mediated regulation extends to other ABHD17A substrates not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether ABHD17A participates in metabolic lipid regulation was unexplored; ABHD17A was found to depalmitoylate SCAP at C264, opposing ZDHHC3, to regulate SCAP stability and cholesterol biosynthesis in hepatocellular carcinoma cells.\",\n      \"evidence\": \"Overexpression/knockdown with acyl-RAC palmitoylation assay, cholesterol biosynthesis assays, ubiquitination assay\",\n      \"pmids\": [\"39522165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of ABHD17A-SCAP axis for cholesterol homeostasis not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The deacylase controlling NOD2 palmitoylation dynamics and its relevance to Crohn's disease variants was unknown; ABHD17A (with 17B/C) was identified as the NOD2 deacylating enzyme, and ABHD17 inhibition restored plasma membrane localization and NF-κB signaling to poorly acylated Crohn's disease-associated NOD2 variants.\",\n      \"evidence\": \"RNAi, small-molecule inhibitors, confocal microscopy, acyl-resin-assisted capture, cytokine multiplex assays\",\n      \"pmids\": [\"40054525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ABHD17 inhibition has therapeutic benefit in Crohn's disease models in vivo not tested\", \"Individual contributions of ABHD17A/B/C to NOD2 deacylation not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How ABHD17A's own membrane targeting is determined was incompletely understood; systematic mutagenesis revealed that middle-region N-terminal cysteines (C14/C15) are critical for plasma membrane delivery and catalytic competence, and a YXXφ motif directs ABHD17A through the trans-Golgi network—disruption reroutes ABHD17A to autophagosomes.\",\n      \"evidence\": \"Alanine scanning mutagenesis, code-restricted mutants, confocal localization, biochemical acylation assays, autophagosome marker co-localization\",\n      \"pmids\": [\"41155484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of autophagosomal mis-targeting on substrate depalmitoylation not quantified\", \"Whether ABHD17A degradation via autophagy is physiologically regulated unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An unconventional role beyond direct depalmitoylation was revealed: ABHD17A interacts with IFITM1 and indirectly increases IFITM1 S-palmitoylation by downregulating the competing depalmitoylase ABHD16A, enhancing IFITM1 antiviral activity.\",\n      \"evidence\": \"Co-IP, palmitoylation assay, overexpression/knockdown with antiviral activity readout, candidate enzyme screen\",\n      \"pmids\": [\"40723864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ABHD17A downregulates ABHD16A not elucidated\", \"Whether this indirect pro-palmitoylation role extends to other substrates unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether ABHD17A deacylates gasdermin family members and contributes to pyroptosis regulation was untested; ABHD17A was shown to deacylate GSDMA, modulating its membrane anchoring and oligomerization relevant to pyroptotic pore formation.\",\n      \"evidence\": \"Acylation assays, overexpression/knockdown with pyroptosis readouts, membrane fractionation\",\n      \"pmids\": [\"41972293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ABHD17A regulates other gasdermin family members not assessed\", \"Reconstitution with purified components not performed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The palmitoylation cycle of METTL3 and its functional consequences were unknown; ABHD17A was identified as the depalmitoylase opposing ZDHHC24-mediated METTL3 palmitoylation at C376, controlling METTL3 condensate formation near ribosomes and its degradation via chaperone-mediated autophagy, with therapeutic relevance in osteoarthritis.\",\n      \"evidence\": \"Palmitoylation assay, Co-IP, AI-guided small-molecule screen, condensate imaging, autophagy assays, OA mouse model\",\n      \"pmids\": [\"41719123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether disruption of ABHD17A–METTL3 interaction affects m6A modification broadly not determined\", \"Specificity of the Isoborneol small molecule for METTL3–ABHD17A not fully characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No crystal or cryo-EM structure of ABHD17A exists, leaving the structural basis for its broad yet site-specific substrate recognition unresolved; the relative non-redundant contributions of ABHD17A versus 17B and 17C across tissues remain poorly defined; and whether ABHD17A loss causes a discrete in vivo phenotype or disease in animal models has not been established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ABHD17A\", \"Genetic knockout phenotype in animal models not reported\", \"Quantitative substrate preference hierarchy not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 6, 8, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 6, 8, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PSD95\",\n      \"NRAS\",\n      \"NLRP3\",\n      \"TEAD1\",\n      \"SCAP\",\n      \"NOD2\",\n      \"METTL3\",\n      \"IFITM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}