ABHD14B

ABHD14B is a serine hydrolase that functions as a lysine deacetylase (KDAC), transferring an acetyl group from post-translationally acetylated protein lysine residues onto coenzyme A to generate acetyl-CoA while regenerating the free lysine amine (PMID:31478652). Through this deacetylation/acetyl-transfer activity it acts as a regulator of central carbon metabolism: loss of ABHD14B reduces flux of glucose through glycolysis and the citric acid cycle in mammalian cells, and hepatic depletion in mice produces defective systemic glucose metabolism that is most pronounced during fasting (PMID:35700823). The same KDAC activity is deployed in an antiviral context, where ABHD14B is recruited to hepatitis B virus covalently closed circular DNA (cccDNA) via the cccDNA-binding factor TFII-I and deacetylates cccDNA-associated histones to suppress HBV RNA transcription (PMID:40658808). Sequence determinants that distinguish ABHD14B from the closely related, functionally unannotated ABHD14A have been defined, supporting its specific assignment as the KDAC-active enzyme of the pair (PMID:37974539).

1. 2019 High

   Established the molecular activity of ABHD14B, resolving a previously orphan serine hydrolase into a defined lysine deacetylase that channels protein acetyl groups onto CoA to make acetyl-CoA.

   Evidence In vitro biochemical assay with recombinant human protein plus mammalian cell knockdown and active-site analysis

   PMID:31478652

   Open questions at the time

   • Endogenous physiological substrate lysines not identified
   • Substrate binding site described as putative, not structurally validated against a bound substrate
2. 2022 High

   Connected the KDAC activity to a physiological output by showing ABHD14B controls glucose flux, demonstrating its enzymatic role is metabolically consequential at the cellular and organismal level.

   Evidence siRNA knockdown with transcriptomics/metabolomics in cells, and hepatic depletion with metabolic phenotyping in mice

   PMID:35700823

   Open questions at the time

   • Direct substrate(s) linking deacetylation to glycolytic/TCA flux not pinpointed
   • Mechanism by which acetyl-CoA generation drives the metabolic phenotype not dissected
3. 2023 Medium

   Resolved the ambiguity between two highly similar paralogs, defining sequence determinants that assign KDAC activity specifically to ABHD14B and not ABHD14A.

   Evidence Bioinformatics sequence analysis combined with biochemical experiments

   PMID:37974539

   Open questions at the time

   • Function of ABHD14A remains unannotated
   • Single-lab classification, partial mechanistic detail
4. 2025 Medium

   Extended ABHD14B function to host antiviral defense, showing its deacetylase activity acts on chromatinized viral cccDNA to repress transcription via a defined recruitment factor.

   Evidence CRISPR dCas9-BioID2 proximity labeling, gene knockout, HBV RNA transcription and histone acetylation assays

   PMID:40658808

   Open questions at the time

   • Single-lab, single study with mechanistic chain partly inferred
   • Specific histone lysine residues deacetylated on cccDNA not mapped
   • TFII-I-ABHD14B interaction not independently validated

• The endogenous protein substrate repertoire that links ABHD14B deacetylation to glucose metabolism remains undefined.
• No physiological substrate lysines identified
• Structural basis of substrate selectivity unresolved
• Relationship between metabolic and antiviral roles unexplored