ABHD17C

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).

1. 2015 High

   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

   PMID:26701913

   Open questions at the time

   • 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
2. 2023 Medium

   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

   PMID:37993419

   Open questions at the time

   • 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
3. 2024 Medium

   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

   PMID:39262472

   Open questions at the time

   • Whether the oncogenic phenotype is mediated through specific ABHD17C depalmitoylase substrates was not tested
   • Generalizability beyond pancreatic cancer cell lines is unconfirmed
4. 2025 High

   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

   PMID:40054525

   Open questions at the time

   • 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
5. 2025 Medium

   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

   PMID:40569151

   Open questions at the time

   • 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
6. 2025 Medium

   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

   PMID:41155484

   Open questions at the time

   • 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

• 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.
• 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