Affinage

ABHD16A

Phosphatidylserine lipase ABHD16A · UniProt O95870

Length
558 aa
Mass
63.2 kDa
Annotated
2026-04-28
15 papers in source corpus 11 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ABHD16A is a serine hydrolase with dual metabolic functions: it acts as a phosphatidylserine lipase generating lysophosphatidylserine (lyso-PS), and as a protein depalmitoylase that removes S-palmitoyl groups from IFITM antiviral proteins. As a PS lipase localized to the endoplasmic reticulum, ABHD16A is the primary source of lyso-PS in the brain, operating in a metabolic axis with ABHD12 to regulate lyso-PS levels; its lyso-PS product signals through GPR34 to activate RhoA/LIMK/cofilin signaling (PMID:25580854, PMID:32462874, PMID:33875796). As a depalmitoylase, ABHD16A removes S-palmitoyl modifications from IFITM1, IFITM2, and IFITM3, dampening their antiviral activity against both RNA and DNA viruses; this depalmitoylase function is negatively regulated by RNF5-mediated ubiquitination at K3 and K452, which targets ABHD16A for proteasomal degradation (PMID:36314839, PMID:40434075, PMID:39601593). Bi-allelic loss-of-function variants in ABHD16A cause hereditary spastic paraplegia with intellectual disability (PMID:34587489).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2014 High

    Establishing the enzymatic identity of ABHD16A: recombinant protein was shown to possess monoacylglycerol lipase activity with defined substrate preferences, demonstrating it is an active serine hydrolase rather than a catalytically dead member of the α/β-hydrolase family.

    Evidence Fluorescent glycerol assay with recombinant ABHD16A, kinetic characterization, and inhibitor profiling in HEK293 cells

    PMID:25290914

    Open questions at the time
    • Physiological substrate in vivo was not identified; in vitro specificity for MAGs did not predict PS lipase activity
    • No structural model explaining substrate selectivity
  2. 2015 High

    Identifying the physiological substrate and metabolic axis: ABHD16A was discovered to be the major PS lipase producing immunomodulatory lyso-PS in vivo, working opposite to ABHD12 which degrades lyso-PS, thereby establishing the ABHD16A–ABHD12 metabolic axis controlling neuroinflammatory lipid signaling.

    Evidence ABPP, Abhd16a knockout mice showing decreased brain lyso-PS, and macrophage cytokine assays

    PMID:25580854

    Open questions at the time
    • Lyso-PS receptor mediating downstream signaling was not identified in this study
    • Tissue-specific contributions of ABHD16A to lyso-PS pools beyond brain and macrophages were unexplored
  3. 2020 High

    Resolving subcellular localization: ABHD16A was localized to the endoplasmic reticulum, and the cerebellum was identified as the brain region most dependent on ABHD16A for lyso-PS production, linking ER-resident lipase activity to region-specific lipid metabolism.

    Evidence Subcellular fractionation, immunofluorescence with KO controls, and cerebellar lipidomics in Abhd16a-/- mice

    PMID:32462874

    Open questions at the time
    • How ER-generated lyso-PS reaches the extracellular space or plasma membrane for signaling was not determined
    • Whether ABHD16A also localizes to other compartments in non-neuronal cells was not resolved
  4. 2021 Medium

    Connecting lyso-PS to a specific signaling pathway: ABHD16A-generated lyso-PS was shown to activate RhoA through GPR34/Gi, driving LIMK/cofilin-mediated cancer cell invasion, and a positive feedback loop via an intronic miRNA (miR-4646-5p) sustaining ABHD16A expression was uncovered.

    Evidence Lipid metabolomics, RhoA/LIMK/cofilin signaling assays, GPR34 pathway analysis, and miRNA functional assays in gastric cancer cells

    PMID:33875796

    Open questions at the time
    • GPR34 pathway placement relies on a single cancer cell model; generalizability to normal physiology not established
    • The miR-4646-5p/PHD3/HIF1A feedback loop awaits independent replication
  5. 2021 Medium

    Establishing a human disease link: bi-allelic loss-of-function ABHD16A variants were shown to cause hereditary spastic paraplegia with intellectual disability, confirming the gene's essential role in CNS development.

    Evidence Whole-exome sequencing in multiple families with Sanger validation and immunoblot confirmation of absent protein in patient fibroblasts

    PMID:34587489

    Open questions at the time
    • Whether disease pathology is driven by lyso-PS deficiency, aberrant palmitoylation, or both was not determined
    • No rescue experiment was performed to confirm causality beyond genetics
  6. 2022 High

    Revealing a second enzymatic function: ABHD16A was identified as a depalmitoylase for IFITM proteins, establishing a direct role in innate antiviral immunity by removing S-palmitoyl groups that are required for IFITM antiviral activity.

    Evidence APEGS depalmitoylation assay in ABHD16A knockout and overexpression cells, with functional antiviral readout against RNA viruses

    PMID:36314839

    Open questions at the time
    • Whether depalmitoylase and PS lipase activities use the same catalytic site or represent distinct reaction mechanisms was not addressed
    • Full spectrum of palmitoylated substrates beyond IFITMs is unknown
  7. 2024 Medium

    Identifying a regulatory mechanism for ABHD16A turnover: RNF5-mediated ubiquitination at K3 and K452 targets ABHD16A for proteasomal degradation, providing a mechanism by which cells can restore IFITM1 antiviral function by eliminating the depalmitoylase.

    Evidence Co-immunoprecipitation, ubiquitination assay with site-directed mutagenesis, proteasome inhibitor experiments, and antiviral assays in swine cells

    PMID:39601593

    Open questions at the time
    • Demonstrated in swine system; conservation of RNF5-ABHD16A axis in human cells not confirmed
    • Physiological signals triggering RNF5-mediated degradation of ABHD16A are unknown
  8. 2025 Medium

    Extending the depalmitoylase function to DNA viruses and identifying ABHD17A as an indirect regulator: ABHD16A-mediated depalmitoylation of IFITM1 was shown to dampen anti-HBV activity, and ABHD17A was found to counteract ABHD16A by promoting its downregulation rather than by direct palmitoylation of IFITMs.

    Evidence CRISPR/Cas9 knockout of ABHD16A in HepG2.215 cells with HBV replication assay; ABHD17A overexpression/knockdown with APEGS assay

    PMID:40434075 PMID:40723864

    Open questions at the time
    • Mechanism by which ABHD17A downregulates ABHD16A protein is unresolved
    • Whether ABHD16A depalmitoylates non-IFITM substrates relevant to viral defense is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how the dual enzymatic activities (PS lipase vs. depalmitoylase) are coordinated or regulated in different cellular contexts, (2) the full palmitoyl-proteome regulated by ABHD16A, and (3) whether the hereditary spastic paraplegia phenotype arises from impaired lyso-PS signaling, aberrant protein palmitoylation, or both.
  • No structural model of ABHD16A exists to explain dual substrate specificity
  • Relative contributions of lipase vs. depalmitoylase activity to CNS disease are not delineated
  • Comprehensive palmitoyl-proteomics in ABHD16A knockout cells has not been performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
GO:0008289 lipid binding 3 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3
Partners
ABHD17AGPR34IFITM1IFITM2IFITM3RNF5

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ABHD16A was identified as a phosphatidylserine (PS) lipase that generates lysophosphatidylserine (lyso-PS) in mammalian systems. Genetic deletion of Abhd16a in mice decreased brain lyso-PS levels, while disruption of ABHD16A in mouse macrophages decreased LPS-induced cytokine production, establishing an ABHD16A-ABHD12 metabolic axis regulating lyso-PS levels in vivo. Activity-based protein profiling (ABPP), pharmacological inhibition, genetic knockout mice (Abhd16a-/-), lipidomics, cytokine measurements in macrophages Nature chemical biology High 25580854
2014 ABHD16A (BAT5) exhibits monoacylglycerol (MAG) lipase activity in vitro, preferentially hydrolyzing long-chain unsaturated MAGs (1-linoleylglycerol, 15d-PGJ2-G) with low-micromolar Km values, with neutral pH optimum and preference for 1(3)- over 2-isomers; it has only marginal diacylglycerol, triacylglycerol, or lysophospholipase activity. Fluorescent glycerol assay with recombinant human and mouse ABHD16A expressed in HEK293 cells; activity-based protein profiling (ABPP); kinetic characterization; inhibitor profiling PloS one High 25290914
2020 ABHD16A is localized to the endoplasmic reticulum (ER) in mammalian cells, as determined by subcellular organelle fractionation and immunofluorescence microscopy; cerebellar lyso-PS levels are most reduced by Abhd16a knockout, establishing that ER-localized ABHD16A is the primary source of lyso-PS in the cerebellum. Subcellular organelle fractionation, biochemical assays, immunofluorescence microscopy, immunohistochemistry with Abhd16a knockout mouse controls, mass spectrometry-based lipidomics Biochemistry High 32462874
2022 ABHD16A functions as a depalmitoylase that catalyzes the removal of S-palmitoyl groups from IFITM proteins (IFITM1, IFITM2, IFITM3), thereby decreasing their antiviral activity against RNA viruses; ABHD16A also regulates the subcellular localization of IFITM proteins. Acyl-PEGyl exchange gel shift (APEGS) assay in abhd16a-/- knockout cells and ABHD16A-overexpressing cells; antiviral activity assays mBio High 36314839
2021 ABHD16A-generated lyso-PS activates RhoA and downstream LIMK/cofilin signaling cascade through GPR34/Gi subunit, promoting gastric cancer cell invasion and metastasis; miR-4646-5p, derived from intron 3 of ABHD16A with the aid of SRSF2, positively feeds back to regulate ABHD16A expression via PHD3/HIF1A stabilization. Lipid metabolomics, RhoA/LIMK/cofilin signaling assays, GPR34 pathway analysis, miRNA functional assays, co-immunoprecipitation, invasion/migration assays Cell death and differentiation Medium 33875796
2021 Bi-allelic loss-of-function variants in ABHD16A cause hereditary spastic paraplegia with intellectual disability; immunoblot analysis of fibroblasts from affected individuals confirmed absent or greatly reduced ABHD16A protein, establishing ABHD16A as essential for normal CNS development and function. Whole-exome sequencing, Sanger validation, immunoblot analysis of patient fibroblasts American journal of human genetics Medium 34587489
2024 Swine RNF5 (E3 ubiquitin ligase) physically interacts with ABHD16A and ubiquitinates it at residues K3 and K452, targeting it for proteasomal degradation, thereby relieving ABHD16A-mediated depalmitoylation of IFITM1 and restoring its antiviral activity. AlphaFold2-based protein interaction prediction, co-immunoprecipitation, immunofluorescence, ubiquitination assay, proteasome inhibitor experiments, APEGS depalmitoylation assay, antiviral activity assays Journal of virology Medium 39601593
2025 ABHD16A catalyzes the depalmitoylation of IFITM1 in HepG2.215 cells, and CRISPR/Cas9 knockout of ABHD16A enhances anti-HBV activity of IFITM1, demonstrating that ABHD16A-mediated depalmitoylation negatively regulates IFITM1 antiviral function against DNA viruses as well as RNA viruses. Co-immunoprecipitation, APEGS assay, CRISPR/Cas9 knockout of IFITM1 and ABHD16A, HBV replication assay Microbiology spectrum Medium 40434075
2025 ABHD17A downregulates ABHD16A protein levels, thereby counteracting ABHD16A-mediated depalmitoylation of IFITM1 and increasing IFITM1 S-palmitoylation and antiviral activity; ABHD17A physically interacts with IFITM1 and lacks the DHHC palmitoylating motif, so its effect on IFITM1 palmitoylation is indirect via ABHD16A suppression. Co-immunoprecipitation, APEGS S-palmitoylation assay, overexpression and knockdown experiments, sequence alignment Biomolecules Medium 40723864
2021 IFITM3 interacts directly with ABHD16A (confirmed by yeast two-hybrid) and co-localizes with ABHD16A at the cell membrane; co-expression of IFITM3 and ABHD16A reduces inflammatory cytokine mRNA levels (IL-1β, IL-6, IL-10, TNF-α) compared to single expression, suggesting functional interplay in inflammatory regulation. NOTE: The original paper (PMID:33763481) was subsequently retracted (PMID:35434131). Yeast two-hybrid, laser confocal co-localization, fluorescent quantitative PCR BioMed research international Low 33763481 35434131

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay. Nature chemical biology 126 25580854
2014 Biochemical and pharmacological characterization of the human lymphocyte antigen B-associated transcript 5 (BAT5/ABHD16A). PloS one 42 25290914
2021 Mirtronic miR-4646-5p promotes gastric cancer metastasis by regulating ABHD16A and metabolite lysophosphatidylserines. Cell death and differentiation 33 33875796
2018 Sequence analysis and structure prediction of ABHD16A and the roles of the ABHD family members in human disease. Open biology 33 29794032
2020 Mapping the Neuroanatomy of ABHD16A, ABHD12, and Lysophosphatidylserines Provides New Insights into the Pathophysiology of the Human Neurological Disorder PHARC. Biochemistry 27 32462874
2022 ABHD16A Negatively Regulates the Palmitoylation and Antiviral Function of IFITM Proteins. mBio 21 36314839
2021 ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies. American journal of human genetics 17 34587489
2025 The Unconventional Role of ABHD17A in Increasing the S-Palmitoylation and Antiviral Activity of IFITM1 by Downregulating ABHD16A. Biomolecules 6 40723864
2024 Swine RNF5 positively regulates the antiviral activity of IFITM1 by mediating the degradation of ABHD16A. Journal of virology 4 39601593
2021 Human Interferon Inducible Transmembrane Protein 3 (IFITM3) Inhibits Influenza Virus A Replication and Inflammation by Interacting with ABHD16A. BioMed research international 4 33763481
2025 Depalmitoylase ABHD16A negatively regulates the anti-hepatitis B virus activity of IFITM1. Microbiology spectrum 3 40434075
2023 Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12. ACS medicinal chemistry letters 3 37849541
1995 Identification of a recombinational breakpoint at the BAT5 locus in three intra-H-2 recombinant inbred mouse strains. Experimental and clinical immunogenetics 3 8919359
2026 Expansion of the genetic and phenotypic spectrum of hereditary spastic paraplegia caused by ABHD16A gene variants: an integrated analysis based on novel variants and literature review. Frontiers in pediatrics 0 41561502
2022 Retracted: Human Interferon Inducible Transmembrane Protein 3 (IFITM3) Inhibits Influenza Virus A Replication and Inflammation by Interacting with ABHD16A. BioMed research international 0 35434131