ABHD17A

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).

1. 2015 High

   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

   PMID:26701913

   Open questions at the time

   • 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
2. 2016 High

   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

   PMID:27307232

   Open questions at the time

   • Whether ABHD17A selectively acts on PSD-95 versus other postsynaptic palmitoylated proteins not tested
   • In vivo behavioral consequences of ABHD17 loss not assessed
3. 2017 Medium

   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

   PMID:28521134

   Open questions at the time

   • Direct biochemical reconstitution of ABHD17A–MAP6 depalmitoylation not performed
   • Whether ABHD17A acts at a specific palmitoylation site on MAP6 not determined
4. 2019 Medium

   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

   PMID:31043565

   Open questions at the time

   • Endogenous ABHD17A regulation downstream of Nf2/Merlin not fully mapped
   • Relative contribution of ABHD17A versus APT2 in TEAD depalmitoylation not quantified
5. 2020 Medium

   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

   PMID:32913120

   Open questions at the time

   • Structural determinants of ABHD17A domain selectivity unknown
   • In vivo consequences for BK channel physiology not assessed
6. 2021 Medium

   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

   PMID:34663815

   Open questions at the time

   • Whether ABHD17A-mediated depalmitoylation of CNAβ1 affects downstream calcineurin signaling not directly tested
7. 2023 High

   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

   PMID:38092000

   Open questions at the time

   • Whether ABHD17A loss alone is sufficient for autoinflammatory disease in vivo not shown
   • Precise structural interface of ABHD17A–NLRP3 interaction not determined
8. 2024 Medium

   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

   PMID:39277583

   Open questions at the time

   • Phosphorylation site(s) on ABHD17A not mapped
   • Whether PI3K-mediated regulation extends to other ABHD17A substrates not tested
9. 2024 Medium

   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

   PMID:39522165

   Open questions at the time

   • In vivo relevance of ABHD17A-SCAP axis for cholesterol homeostasis not confirmed
10. 2025 Medium

    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

    PMID:40054525

    Open questions at the time

    • 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
11. 2025 Medium

    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

    PMID:41155484

    Open questions at the time

    • Functional consequences of autophagosomal mis-targeting on substrate depalmitoylation not quantified
    • Whether ABHD17A degradation via autophagy is physiologically regulated unknown
12. 2025 Medium

    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

    PMID:40723864

    Open questions at the time

    • Mechanism by which ABHD17A downregulates ABHD16A not elucidated
    • Whether this indirect pro-palmitoylation role extends to other substrates unknown
13. 2026 Medium

    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

    PMID:41972293

    Open questions at the time

    • Whether ABHD17A regulates other gasdermin family members not assessed
    • Reconstitution with purified components not performed
14. 2026 Medium

    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

    PMID:41719123

    Open questions at the time

    • Whether disruption of ABHD17A–METTL3 interaction affects m6A modification broadly not determined
    • Specificity of the Isoborneol small molecule for METTL3–ABHD17A not fully characterized

• 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.
• No structural model of ABHD17A
• Genetic knockout phenotype in animal models not reported
• Quantitative substrate preference hierarchy not established