ABHD16A

ABHD16A is an endoplasmic reticulum-localized serine hydrolase of the α/β-hydrolase family that acts as a phosphatidylserine lipase, generating lysophosphatidylserine (lyso-PS) in mammalian brain and immune cells (PMID:25580854, PMID:32462874). In vitro it is a catalytically active lipase with monoacylglycerol hydrolase activity, preferring long-chain unsaturated monoacylglycerols at a neutral pH optimum, and is inhibited by β-lactone and HSL inhibitors at nanomolar concentrations (PMID:25290914). ABHD16A works upstream of and antagonistically to the lyso-PS lipase ABHD12 to set steady-state lyso-PS levels: its deletion lowers brain and cerebellar lyso-PS whereas ABHD12 loss raises it, defining a biosynthesis–degradation axis with regional specificity in the cerebellum (PMID:25580854, PMID:32462874). Lyso-PS produced by ABHD16A is signaling-competent, stimulating RhoA and the downstream LIMK/cofilin cascade through GPR34/Gi to drive gastric cancer cell invasion (PMID:33875796), and supports lipopolysaccharide-induced cytokine production in macrophages (PMID:25580854). Independently of its lipase role, ABHD16A functions as a depalmitoylase that removes palmitate from S-palmitoylated IFITM antiviral proteins (IFITM1/2/3), reducing their palmitoylation, membrane localization, and antiviral activity against RNA viruses and HBV (PMID:36314839, PMID:40434075); this activity is itself controlled by RNF5-mediated ubiquitination at K3 and K452 leading to proteasomal degradation of ABHD16A (PMID:39601593). Bi-allelic loss-of-function variants in ABHD16A cause hereditary spastic paraplegia with intellectual disability, with patient fibroblasts showing little to no ABHD16A protein (PMID:34587489).

1. 2014 Medium

   Established that ABHD16A (BAT5) is a bona fide catalytically active serine hydrolase, answering whether the protein had intrinsic lipase activity and defining its in vitro substrate preference.

   Evidence ABPP, fluorescent glycerol substrate assays, inhibitor SAR, and recombinant expression in HEK293 cells

   PMID:25290914

   Open questions at the time

   • In vitro MAG hydrolase activity did not establish the physiological substrate
   • No cellular or in vivo lipid context provided
   • Phosphatidylserine was not yet identified as the substrate
2. 2015 High

   Identified phosphatidylserine as the physiological substrate and placed ABHD16A upstream of ABHD12 in a lyso-PS biosynthesis–degradation axis, resolving the in vivo function and pathway position.

   Evidence ABPP, pharmacological inhibition, Abhd16a-/- and Abhd12-/- mice, brain lipid mass spectrometry, and macrophage cytokine measurements

   PMID:25580854

   Open questions at the time

   • Subcellular site of lyso-PS generation not yet localized
   • Downstream lyso-PS receptors/signaling not defined
   • Mechanism of antagonism with ABHD12 not structurally resolved
3. 2020 High

   Localized ABHD16A to the ER and demonstrated region- and cell-type-specific functional cross-talk with ABHD12 in the cerebellum, connecting enzymatic activity to anatomical context.

   Evidence Subcellular fractionation, immunofluorescence, immunohistochemistry with KO controls, and quantitative lyso-PS lipidomics across brain regions

   PMID:32462874

   Open questions at the time

   • Does not explain how spatially distinct lipases coordinate lyso-PS pools
   • No link to a neurological phenotype yet
   • Receptor-level signaling consequences not addressed
4. 2021 Medium

   Connected ABHD16A-generated lyso-PS to a defined signaling output, showing it activates GPR34/Gi/RhoA/LIMK/cofilin to promote cancer cell invasion.

   Evidence ABHD16A overexpression/knockdown, lyso-PS measurement, pathway dissection, and invasion assays in gastric cancer cells

   PMID:33875796

   Open questions at the time

   • Single tumor context
   • Direct receptor engagement by ABHD16A-derived lyso-PS not biochemically isolated
   • In vivo metastasis dependence on ABHD16A not fully established
5. 2021 Medium

   Established ABHD16A as the molecular cause of a Mendelian neurological disorder, linking loss of the PS lipase to disease in humans.

   Evidence Whole-exome sequencing of 11 affected individuals, Sanger validation, and immunoblot of patient fibroblasts showing loss of protein

   PMID:34587489

   Open questions at the time

   • Pathophysiology linking lyso-PS dysregulation to spastic paraplegia not mechanistically demonstrated
   • Mechanism inferred from prior enzymatic work rather than directly tested in neurons
   • Genotype-phenotype correlation limited
6. 2022 High

   Revealed a second, lipase-independent activity—ABHD16A depalmitoylates IFITM antiviral proteins—expanding its substrate scope beyond phospholipids to protein S-acylation.

   Evidence APEGS palmitoylation assay in ABHD16A KO and overexpression cells across species, with antiviral and localization readouts

   PMID:36314839

   Open questions at the time

   • Structural basis distinguishing lipase vs depalmitoylase activity unresolved
   • Whether ER localization governs IFITM access not addressed
   • Endogenous regulation of the depalmitoylase activity not yet defined
7. 2024 Medium

   Defined how ABHD16A's depalmitoylase activity is itself regulated, showing RNF5-mediated ubiquitination at K3/K452 drives its proteasomal degradation to restore IFITM antiviral function.

   Evidence AlphaFold2 interaction prediction, co-IP, ubiquitination assays with site mapping, proteasome inhibition, and antiviral readouts

   PMID:39601593

   Open questions at the time

   • Single-lab co-IP-based interaction
   • Physiological stimulus triggering RNF5-mediated degradation unclear
   • Conservation of K3/K452 regulation in human cells not established
8. 2025 Medium

   Extended the ABHD16A–IFITM regulatory network, showing ABHD17A counteracts ABHD16A by downregulating its expression and confirming ABHD16A depalmitoylation negatively regulates IFITM1 anti-HBV activity in hepatocytes.

   Evidence Co-IP, Western blotting, APEGS assays, CRISPR/Cas9 KO, and viral replication assays in HepG2.215 cells

   PMID:40434075 PMID:40723864

   Open questions at the time

   • Mechanism of ABHD17A-mediated ABHD16A downregulation incompletely resolved
   • Single-lab studies
   • Interplay between depalmitoylase and lipase functions in vivo untested

• How ABHD16A reconciles its two distinct catalytic activities (PS lipase vs IFITM depalmitoylase) and how lyso-PS dysregulation produces the neurological disease phenotype remain unresolved.
• No structural model distinguishing the two activities
• Neuronal mechanism connecting lyso-PS to spastic paraplegia not demonstrated
• Tissue-specific balance between lipase and depalmitoylase roles unknown