ABHD17B

ABHD17B is a serine hydrolase that functions as an acyl protein thioesterase (depalmitoylase), removing S-palmitoyl modifications from diverse substrates including N-Ras, PSD95, NOD2, hexokinase 1 (HK1), and ASCT2, thereby controlling their membrane association, subcellular localization, and downstream signaling (PMID:26701913, PMID:40054525, PMID:36192599, PMID:41730846). Its own plasma membrane targeting depends on palmitoylation of conserved N-terminal cysteine residues, with middle-region cysteines being critical for catalytic competence (PMID:41155484). In hepatic stellate cells, ABHD17B is transcriptionally activated by the nuclear receptor Nur77 and depalmitoylates HK1 to attenuate its secretion via large extracellular vesicles; ABHD17B also promotes fibrotic gene expression and cell migration through a depalmitoylation-independent interaction with MYO1B, and its depletion protects mice from liver fibrosis (PMID:36192599, PMID:40025044).

1. 2015 High

   Identification of ABHD17 proteins as bona fide depalmitoylases for N-Ras and PSD95 resolved which thioesterases govern palmitate turnover on these substrates, distinguishing them from the previously characterized APT1/APT2 enzymes.

   Evidence Dual pulse-chase palmitate/protein half-life assays, activity-based serine hydrolase profiling, knockdown, and imaging in mammalian cells

   PMID:26701913

   Open questions at the time

   • Full substrate repertoire of ABHD17B beyond N-Ras and PSD95 was unknown
   • Structural basis for substrate recognition not determined
   • Relative contributions of ABHD17A, B, and C to depalmitoylation were not deconvolved
2. 2022 High

   Demonstrating that ABHD17B depalmitoylates HK1 in hepatic stellate cells and is transcriptionally controlled by Nur77 established a signaling axis (TGF-β → Akt → Nur77 → ABHD17B → HK1) linking metabolic signaling to extracellular vesicle-mediated HK1 secretion.

   Evidence Palmitoylation assays, extracellular vesicle fractionation, transcriptional reporters, and Akt modulation in hepatic stellate cells

   PMID:36192599

   Open questions at the time

   • Whether Nur77-dependent transcriptional regulation of ABHD17B operates in cell types beyond hepatic stellate cells was not tested
   • Direct enzymatic kinetics of ABHD17B on HK1 not measured
3. 2025 High

   Showing that ABHD17 family members depalmitoylate NOD2 to displace it from membranes and dampen NF-κB signaling extended the substrate scope to innate immune receptors and revealed a functional role in controlling inflammatory cytokine output.

   Evidence RNAi, chemical inhibitors, acyl-RAC, confocal microscopy, and cytokine multiplex assays in engineered cell lines

   PMID:38187608 PMID:40054525

   Open questions at the time

   • Individual contribution of ABHD17B versus ABHD17A/C to NOD2 depalmitoylation not fully resolved
   • In vivo relevance for inflammatory bowel disease or other NOD2-linked disorders not established
4. 2025 Medium

   Discovery that ABHD17B promotes hepatic stellate cell fibrotic activation partly through a depalmitoylation-independent interaction with MYO1B revealed a non-catalytic function that regulates cell migration and fibrogenic gene expression.

   Evidence High-throughput siRNA screen in primary human HSC myofibroblasts, co-IP with MYO1B, gene expression analysis, and in vivo mouse liver injury model

   PMID:40025044

   Open questions at the time

   • MYO1B interaction validated only by co-IP in a single study; reciprocal pull-down or domain mapping not reported
   • Mechanism by which ABHD17B–MYO1B interaction modulates gene expression is undefined
   • Whether the non-catalytic role is specific to hepatic stellate cells is unknown
5. 2025 Medium

   Mutagenesis of the conserved N-terminal cysteine cluster demonstrated that middle-region palmitoylation sites are essential for plasma membrane targeting and catalytic function of the ABHD17 family, clarifying how the enzyme reaches its substrates.

   Evidence Alanine scanning of N-terminal cysteines, confocal microscopy, and acylation assays; conservation in ABHD17B confirmed by mutagenesis

   PMID:41155484

   Open questions at the time

   • ABHD17B-specific mutagenesis was secondary to ABHD17A-focused analysis
   • Which palmitoyltransferase(s) modify ABHD17B N-terminal cysteines is unknown
6. 2026 Medium

   Identification of ASCT2 as an ABHD17B substrate showed that depalmitoylation by ABHD17B stabilizes ASCT2 protein by preventing its lysosomal degradation, linking ABHD17B to glutamine transporter homeostasis.

   Evidence Palmitoylation assays, Cys39/Cys48 mutagenesis, ABHD17B and ZDHHC14 overexpression/knockdown, protein degradation assays

   PMID:41730846

   Open questions at the time

   • Single study; independent replication needed
   • Physiological consequences of ASCT2 stabilization by ABHD17B (e.g., on glutamine metabolism) not explored
   • Whether ABHD17A/C share this substrate specificity is untested

• No crystal or cryo-EM structure of ABHD17B has been reported, and the structural basis for its broad substrate recognition, the determinants distinguishing it from ABHD17A/C, and the mechanism of its non-catalytic MYO1B-dependent functions remain open questions.
• No structural model of ABHD17B
• Paralog-specific substrate selectivity among ABHD17A/B/C not systematically mapped
• In vivo genetic models (knockout mice) for ABHD17B specifically have not been characterized