ABHD8 is a cytoplasmic alpha/beta-hydrolase-fold protein. It retains a full predicted Ser/Asp/His charge relay system and is placed in MEROPS family S33, and phylogenetically inferred lipid hydrolase functions, although a target-specific catalytic activity has not been demonstrated: UniProt assigns only a generic hydrolase EC number and records no reaction or substrate. Its experimentally characterised function is adaptor-like: ABHD8 binds NLRP3 through the sensor's NACHT and LRR domains, an interaction strengthened by inflammasome inducers such as ATP, nigericin, silica and alum, and recruits the palmitoyltransferase ZDHHC12 to it. The resulting palmitoylation routes NLRP3 into chaperone-mediated autophagy, so the sensor is degraded and inflammasome activation and IL-1beta secretion are damped. Loss of ABHD8 stabilises NLRP3 and promotes inflammasome activation, while overexpression attenuates LPS- and alum-triggered activation in vivo. The axis is a target of viral antagonism: the SARS-CoV-2 nucleocapsid protein disrupts the ABHD8-NLRP3 association, stabilising NLRP3 and driving excessive inflammasome activation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004620 glycerophospholipase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the phylogenetically inferred hydrolase activity alongside the demonstrated NLRP3 adaptor function. Reason: PTHR42886 places glycerophospholipase and carboxylic-ester hydrolase activities at PTN008676419, with experimental descendant grounding in several lineages including mouse Abhd4 and yeast Cld1. This is an ancestral-function assertion, not an unsupported pairwise transfer. PMID:26745266 challenges the plant CGI-58 catalytic evidence, but does not invalidate the other hydrolase branches or establish an ABHD8-specific loss; ABHD8 retains the predicted catalytic triad. PMID:39225180 demonstrates an adaptor mechanism without assaying and excluding lipid hydrolase activity. The focused report will assess the contested source and target assays; absence of an ABHD8 assay alone does not justify over-annotation. Supporting Evidence: PMID:26745266 recombinant plant CGI-58 does not catalyze TAG or phospholipid hydrolysis. |
| GO:0052689 carboxylic ester hydrolase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the phylogenetically inferred hydrolase activity alongside the demonstrated NLRP3 adaptor function. Reason: PTHR42886 places glycerophospholipase and carboxylic-ester hydrolase activities at PTN008676419, with experimental descendant grounding in several lineages including mouse Abhd4 and yeast Cld1. This is an ancestral-function assertion, not an unsupported pairwise transfer. PMID:26745266 challenges the plant CGI-58 catalytic evidence, but does not invalidate the other hydrolase branches or establish an ABHD8-specific loss; ABHD8 retains the predicted catalytic triad. PMID:39225180 demonstrates an adaptor mechanism without assaying and excluding lipid hydrolase activity. The focused report will assess the contested source and target assays; absence of an ABHD8 assay alone does not justify over-annotation. Supporting Evidence: PMID:26745266 recombinant plant CGI-58 does not catalyze TAG or phospholipid hydrolysis. |
| GO:0055088 lipid homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain lipid homeostasis as a non-core ancestral process inference, distinct from a specific catalytic reaction. Reason: PTN008676419 has a lipid-homeostasis IBD supported by Arabidopsis CGI-58. PMID:26745266 refutes several proposed recombinant catalytic activities while retaining an effect on phosphatidylglycerol in cells and discussing established lipid-homeostasis phenotypes. Thus catalytic-source controversies do not by themselves erase the process evidence. No ABHD8-specific loss of this broader ancestral role is established, although its best characterized role is NLRP3 control. Supporting Evidence: PMID:26745266 expression of recombinant plant CGI-58, but not mouse CGI-58, led to a decrease in phosphatidylglycerol in all strains of E. coli tested |
| GO:0006654 phosphatidic acid biosynthetic process | IBA GO_REF:0000033 | UNDECIDED | Summary: The LPA-acyltransferase/PA-biosynthesis inference has a substantive source conflict and remains unresolved. Reason: The IBD at PTN008676419 includes human ABHD5 and yeast Ict1 for PA biosynthesis, with plant CGI-58 also contributing to LPA acyltransferase. PMID:24879803 attributes earlier recombinant CGI-58 LPAAT activity to bacterial PlsC contamination and also reports no activity for human CGI-58 expressed in yeast. PMID:26745266 independently disputes plant CGI-58 acyltransferase activity. These are source-side conflicts, not donor-count objections; yeast Ict1 support remains to be adjudicated. Target-specific PMID:39225180 notes absence of the HXXXXD acyltransferase motif and demonstrates recruitment of ZDHHC12, but does not test every possible PA-producing role. Leave each claim unresolved instead of presenting all source activities as established or inferring loss solely from the adaptor role. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN008676419 · PTN008676419 UNRESOLVED ABHD5 and plant CGI-58 catalytic evidence is directly challenged by later controlled assays; Ict1 and target-specific chemistry require assessment. The biosynthetic process is considered separately from the reaction. Supporting Evidence: PMID:24879803 human CGI-58 expressed in yeast lacked LPAAT activity. PMID:39225180 ABHD8 lacks of the acyltransferase activity motif (HXXXXD) |
| GO:0042171 lysophosphatidic acid acyltransferase activity | IBA GO_REF:0000033 | UNDECIDED | Summary: The LPA-acyltransferase/PA-biosynthesis inference has a substantive source conflict and remains unresolved. Reason: The IBD at PTN008676419 includes human ABHD5 and yeast Ict1 for PA biosynthesis, with plant CGI-58 also contributing to LPA acyltransferase. PMID:24879803 attributes earlier recombinant CGI-58 LPAAT activity to bacterial PlsC contamination and also reports no activity for human CGI-58 expressed in yeast. PMID:26745266 independently disputes plant CGI-58 acyltransferase activity. These are source-side conflicts, not donor-count objections; yeast Ict1 support remains to be adjudicated. Target-specific PMID:39225180 notes absence of the HXXXXD acyltransferase motif and demonstrates recruitment of ZDHHC12, but does not test every possible PA-producing role. Leave each claim unresolved instead of presenting all source activities as established or inferring loss solely from the adaptor role. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN008676419 · PTN008676419 UNRESOLVED ABHD5 and plant CGI-58 catalytic evidence is directly challenged by later controlled assays; Ict1 and target-specific chemistry require assessment. The biosynthetic process is considered separately from the reaction. Supporting Evidence: PMID:24879803 human CGI-58 expressed in yeast lacked LPAAT activity. PMID:39225180 ABHD8 lacks of the acyltransferase activity motif (HXXXXD) |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | ACCEPT | Summary: Catalytic activity is a valid broad inference from the retained hydrolase-family function. Reason: The prior review treated absence of an assigned substrate or direct ABHD8 enzymology as evidence of catalytic loss. Conserved catalytic residues and the curated hydrolase IBD support this broad term; the demonstrated adaptor function can coexist with catalysis. No claim of a directly measured ABHD8 reaction is made. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt cytoplasm location, which is experimentally supported (ECO:0000269|PubMed:39225180). Correct core compartment - it is where ABHD8 meets NLRP3. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:39225180}. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Interaction with FNDC3B isoform 3 (UniProtKB:Q53EP0-3) from the human binary interactome reference map. A single large-scale screen hit with no functional follow-up, no described connection to the NLRP3 biology that is the whole of what is known about ABHD8, and an uninformative term. Note the screen recovered neither NLRP3 nor ZDHHC12. Reason: Remove the uninformative generic protein binding term while retaining the reported interactions. This does not dispute the interaction assay and does not infer an additional activity from binding alone. The mechanistically demonstrated NLRP3–ZDHHC12 bridging function is retained under the informative adaptor replacement in row 10. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- FUNCTION: Negatively regulates NLRP3-driven inflammation |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Interaction with ZNF410 isoform 3 (UniProtKB:Q86VK4-3) from the same binary interactome screen, split out as its own entry per the one-entry-per-GOA-row convention. Same assessment as the FNDC3B row: a transcription factor with no described link to inflammasome regulation, no follow-up, uninformative term. Reason: Remove the uninformative generic protein binding term while retaining the reported interactions. This does not dispute the interaction assay and does not infer an additional activity from binding alone. The mechanistically demonstrated NLRP3–ZDHHC12 bridging function is retained under the informative adaptor replacement in row 10. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- FUNCTION: Negatively regulates NLRP3-driven inflammation |
| GO:1900226 negative regulation of NLRP3 inflammasome complex assembly | IEA GO_REF:0000120 | ACCEPT | Summary: Negative regulation of NLRP3 inflammasome complex assembly - the gene's core process and its best-supported annotation. ABHD8 promotes NLRP3 degradation through chaperone-mediated autophagy by recruiting the palmitoyltransferase ZDHHC12 to NLRP3, and ABHD8 deficiency stabilises NLRP3 protein and promotes inflammasome activation. Overexpression ameliorates LPS- and alum-triggered activation in vivo. Note the mechanism is degradation of the sensor rather than interference with assembly per se, so a term about NLRP3 protein stability would arguably fit better; GO offers none, and the downstream effect on assembly is real. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt activation and IL1B secretion. Acts by recruiting palmitoyltransferase PMID:39225180 ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. |
| GO:0005515 protein binding | IPI PMID:39225180 ABHD8 antagonizes inflammation by facilitating chaperone-med... | MODIFY | Summary: Interaction with ZDHHC12 (UniProtKB:Q96GR4) and NLRP3 (UniProtKB:Q96P20) - the two partners that constitute this protein's characterised activity. ABHD8 binds NLRP3 via its NACHT and LRR domains, with the interaction enhanced by inflammasome inducers, and recruits the palmitoyltransferase ZDHHC12 to it, so that NLRP3 is palmitoylated and degraded by chaperone-mediated autophagy. Bare protein binding badly understates this: the interactions ARE the function. This entry covers only the ZDHHC12/NLRP3 row. The SARS-CoV-2 nucleoprotein interaction from the same publication is a separate GOA row and is reviewed separately below, because ABHD8's role there is opposite - it is the target of the disruption, not the adaptor. Reason: Uninformative term for the interactions that constitute this protein's characterised activity. Proposed replacements: enzyme-substrate adaptor activity Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- SUBUNIT: Interacts with NLRP3 (via NACHT and LLR domains); this file:human/ABHD8/ABHD8-uniprot.txt activation and IL1B secretion. Acts by recruiting palmitoyltransferase |
| GO:0005737 cytoplasm | IDA PMID:39225180 ABHD8 antagonizes inflammation by facilitating chaperone-med... | ACCEPT | Summary: Direct localisation of ABHD8 to the cytoplasm in the study that characterised its NLRP3 function. Core compartment, and the one in which the adaptor activity occurs. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:39225180}. |
| GO:1900226 negative regulation of NLRP3 inflammasome complex assembly | IMP PMID:39225180 ABHD8 antagonizes inflammation by facilitating chaperone-med... | ACCEPT | Summary: Negative regulation of NLRP3 inflammasome complex assembly - the gene's core process and its best-supported annotation. ABHD8 promotes NLRP3 degradation through chaperone-mediated autophagy by recruiting the palmitoyltransferase ZDHHC12 to NLRP3, and ABHD8 deficiency stabilises NLRP3 protein and promotes inflammasome activation. Overexpression ameliorates LPS- and alum-triggered activation in vivo. Note the mechanism is degradation of the sensor rather than interference with assembly per se, so a term about NLRP3 protein stability would arguably fit better; GO offers none, and the downstream effect on assembly is real. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt activation and IL1B secretion. Acts by recruiting palmitoyltransferase PMID:39225180 ABHD8 deficiency results in the stabilization of NLRP3 protein and promotes NLRP3 inflammasome activation. |
| GO:0070062 extracellular exosome | HDA PMID:18570454 Proteomic analysis of exosomes from human neural stem cells ... | KEEP AS NON CORE | Summary: Retain the experimentally curated extracellular-exosome observation as non-core. Reason: The HDA annotation records ABHD8 detection in the human neural-stem-cell exosome proteome. Localization in an extracellular vesicle does not require the protein to have an exosomal effector function, and a main cytoplasmic pool does not exclude vesicle association. The available abstract does not independently resolve the individual peptide assignment, so retain the curated proteomic observation without claiming a core secretion mechanism. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:39225180}. |
| GO:0005515 protein binding | IPI PMID:39225180 ABHD8 antagonizes inflammation by facilitating chaperone-med... | REMOVE | Summary: Interaction with the SARS-CoV-2 nucleoprotein N (UniProtKB:P0DTC9), split out from the ZDHHC12/NLRP3 row above because ABHD8's role is the opposite one. N binds ABHD8 and DISRUPTS the ABHD8-NLRP3 association, stabilising NLRP3 and driving excessive inflammasome activation. ABHD8 is the target of viral antagonism here, not an adaptor bringing an enzyme to a substrate - so the enzyme-substrate adaptor term proposed for the host interactions must not be extended to this row, which would invert the direction of the relationship. Kept as a real, mechanistically meaningful interaction under an uninformative term. It is genuine host-pathogen biology from the gene's defining paper, and it is informative about ABHD8 precisely because disrupting the interaction reproduces the ABHD8-null phenotype - but 'protein binding' records none of that, and GO has no obvious better term for being the target of a viral antagonist. Reason: Remove the uninformative generic protein binding term while retaining the reported interactions. This does not dispute the interaction assay and does not infer an additional activity from binding alone. The mechanistically demonstrated NLRP3–ZDHHC12 bridging function is retained under the informative adaptor replacement in row 10. Supporting Evidence: file:human/ABHD8/ABHD8-uniprot.txt CC -!- SUBUNIT: (Microbial infection) Interacts with SARS-CoV-2 nucleoprotein |
Loading supporting content…
Download this section (compressed HTML)Q: Is ABHD8's predicted catalytic triad competent on any substrate? UniProt annotates a full Ser/Asp/His charge relay at residues 252, 370 and 398 and places the protein in MEROPS S33 and ESTHER, so this is not a fold-only prior - but the residues are ECO:0000250, UniProt records no reaction, and no substrate has been reported. Note the contrast with ABHD5, often cited as the alpha/beta-hydrolase-fold protein that is not a hydrolase: ABHD5 has NO annotated active site, whereas ABHD8 has a complete one, so ABHD8 is not an ABHD5-type pseudoenzyme and the analogy does not transfer.
Q: Are the acyltransferase inferences worth retaining? Their WITH/FROM includes yeast ICT1 (SGD:S000004089), a genuine 1-acylglycerol-3-phosphate O-acyltransferase, as well as the human paralog ABHD5 - so the activity is present in more than one family member and this is not simply a paralog artefact. It remains untested in ABHD8, and sits oddly beside the hydrolase activities inferred from the same node.
Q: Is the NLRP3 effect on assembly or on abundance? The demonstrated mechanism is degradation of the sensor via chaperone-mediated autophagy, so reduced inflammasome assembly is a consequence of lower NLRP3 levels. GO:1900226 captures the outcome but not the mechanism, and no term for regulation of NLRP3 protein stability exists.
Q: How general is the viral antagonism? SARS-CoV-2 nucleoprotein disrupting the ABHD8-NLRP3 association is striking; whether other pathogens target the same adaptor step would show how important this brake is to host defence. Note GO also has no good way to record a protein being the target of a viral antagonist, which is why that row keeps a bare binding term.
Experiment: Assay purified ABHD8 by activity-based protein profiling with serine-hydrolase-directed probes, which report triad reactivity independently of knowing the substrate, then follow with broad ester, thioester and lipid panels. In parallel test whether an active-site serine mutant still supports NLRP3 palmitoylation and degradation - if it does, the adaptor role is formally separable from any enzymology. Note this is better posed than asking whether the triad is intact, which UniProt already answers by similarity.
Hypothesis: ABHD8's predicted catalytic triad is competent on some substrate, or the protein is a genuine pseudoenzyme.
Type: enzymology and structure-function
Experiment: Compare NLRP3 palmitoylation kinetics with wild-type ABHD8 against a forced ZDHHC12-NLRP3 fusion that bypasses the adaptor, and against ABHD8 variants that bind one partner but not the other, to distinguish proximity from activation.
Hypothesis: ABHD8 acts by increasing the local concentration of ZDHHC12 at NLRP3 rather than by allosteric activation.
Type: biochemistry
Experiment: Screen nucleocapsid and accessory proteins from a panel of RNA viruses for disruption of the ABHD8-NLRP3 interaction, and correlate disruption with NLRP3 stabilisation and IL-1beta output in macrophages.
Hypothesis: The ABHD8-NLRP3 brake is a general target of viral antagonism.
Type: virology
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)