ABHD17C

ABHD17C is a substrate-specific serine hydrolase that acts as a protein depalmitoylase (acyl protein thioesterase), removing S-palmitoyl groups from target proteins to control their membrane association, subcellular distribution, stability, and downstream signaling (PMID:26701913). Its activity is distinct from APT1/APT2: it catalyzes palmitate removal from N-Ras and PSD95 and drives N-Ras re-localization from the plasma membrane to internal membranes, an activity dependent on its catalytic serine (PMID:26701913). Across multiple contexts, ABHD17C-mediated depalmitoylation acts as a regulatory switch—de-S-acylation of the innate immune receptor NOD2 reduces its plasma membrane localization and dampens NF-κB-driven inflammatory cytokine output, marking ABHD17C as a negative regulator of NOD2 signaling (PMID:40054525, PMID:38187608); depalmitoylation of ALOX15B and of BCL6B (at Cys442) triggers their membrane-to-cytoplasm translocation and subsequent ubiquitin-proteasome degradation, the latter via the CUL4/DDB1/DCAF10 ligase complex (PMID:40569151, PMID:42154583). Its own plasma membrane targeting and catalytic activity require palmitoylation of a conserved middle-region cysteine cluster (PMID:41155484), and the enzyme is post-translationally controlled by USP35-dependent deubiquitination that stabilizes it (PMID:37993419) and by ERK1-mediated phosphorylation downstream of mutant KRAS that promotes its activity (PMID:40569151). Through these substrate-directed actions, ABHD17C influences tumor cell proliferation, ferroptosis sensitivity, and immune evasion in several cancer models (PMID:37993419, PMID:40569151, PMID:42154583).

1. 2015 High

   Established that ABHD17C is a bona fide protein depalmitoylase with substrate specificity distinct from the classical APT1/APT2 thioesterases, answering whether dedicated enzymes beyond APTs control palmitate turnover on signaling proteins.

   Evidence Dual pulse-chase of palmitate vs protein half-life, activity-based serine hydrolase profiling, catalytic mutant and APT1/2 inhibition, live-cell N-Ras imaging

   PMID:26701913

   Open questions at the time

   • Did not define the full substrate repertoire
   • No structural basis for substrate selection
   • Mechanism of in vivo regulation not addressed
2. 2023 Medium

   Showed ABHD17C is post-translationally stabilized by the deubiquitinase USP35, linking enzyme abundance to oncogenic PI3K/AKT signaling and defining a layer of upstream control over its protein levels.

   Evidence Reciprocal Co-IP, ubiquitination assay, USP35 knockdown with ABHD17C rescue, and xenograft in hepatocellular carcinoma cells

   PMID:37993419

   Open questions at the time

   • Single lab, not independently replicated
   • Direct depalmitoylase substrates driving PI3K/AKT effect not identified
   • Whether USP35 acts directly on ABHD17C ubiquitin chains unresolved
3. 2025 High

   Identified the innate immune receptor NOD2 as an ABHD17C substrate, establishing ABHD17 isoforms as negative regulators of NOD2 plasma membrane localization and NF-κB inflammatory signaling.

   Evidence RNAi, small-molecule ABHD17 inhibition, Acyl-RAC, confocal microscopy, and cytokine multiplex assays in engineered epithelial cells

   PMID:38187608 PMID:40054525

   Open questions at the time

   • Isoform-specific contribution of ABHD17C versus A/B not dissected
   • De-S-acylated cysteine site on NOD2 not mapped
   • Physiological/disease relevance in intact tissue not established
4. 2025 Medium

   Connected ABHD17C activity to upstream KRAS-ERK1 signaling and downstream ferroptosis control, showing ERK1 phosphorylation enhances its depalmitoylation of ALOX15B and routes ALOX15B to CUL4/DDB1/DCAF10-dependent degradation.

   Evidence Phosphorylation and palmitoylation assays, ABHD17C/ALOX15B interaction, proteasome inhibition, patient-derived organoids, xenografts, and MPD small-molecule disruption

   PMID:40569151

   Open questions at the time

   • Single lab, limited independent replication
   • Phosphosite(s) on ABHD17C not defined
   • Generalizability beyond the studied cancer context unclear
5. 2025 Medium

   Demonstrated site-specific depalmitoylation of BCL6B (Cys442) by ABHD17C blocks importin-α/β nuclear import and drives BCL6B degradation, derepressing CD24 to enable cancer immune evasion from macrophage phagocytosis.

   Evidence Site-specific depalmitoylation, importin interaction and ubiquitination assays, CD24 promoter/transcription readouts, phagocytosis assays, and orthotopic NSG mouse models

   PMID:42154583

   Open questions at the time

   • Single lab
   • Coordination with other ABHD17C substrate-directed pathways unknown
   • Direct enzyme-substrate engagement structure not resolved
6. 2025 Medium

   Defined how ABHD17C achieves its own membrane localization, showing palmitoylation of a conserved N-terminal/middle-region cysteine cluster is required for plasma membrane targeting and catalytic activity.

   Evidence Alanine-scanning mutagenesis, biochemical acylation assays, and confocal imaging of localization mutants

   PMID:41155484

   Open questions at the time

   • ABHD17C finding secondary to primary ABHD17A study
   • Enzyme(s) palmitoylating ABHD17C not identified
   • Dynamics of self-palmitoylation versus substrate turnover not addressed

• How ABHD17C selects among its diverse substrates (N-Ras, PSD95, NOD2, ALOX15B, BCL6B) and how its phosphorylation, self-palmitoylation, and USP35 stabilization are integrated into a unified regulatory logic remains unresolved.
• No structural model of substrate recognition
• No comprehensive substrate map
• Cross-talk between regulatory inputs not reconstituted