{"gene":"ZDHHC21","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2016,"finding":"DHHC21 palmitoylates PLCβ1 in vascular endothelial cells; inflammation enhances PLCβ1 palmitoylation and signaling activity, effects significantly reduced in Zdhhc21dep/dep mice and rescued by DHHC21 overexpression. Overexpression of wild-type but not catalytically mutant PLCβ1 augmented barrier dysfunction, placing DHHC21-mediated PLCβ1 palmitoylation upstream of endothelial junction hyperpermeability and ICAM-1 expression.","method":"Zdhhc21dep/dep mice (loss-of-function), DHHC21 overexpression rescue, palmitoylation assay, endothelial permeability assay, leukocyte adhesion assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function mouse model plus overexpression rescue with wild-type vs. mutant constructs across multiple orthogonal functional readouts, replicated in vitro and in vivo","pmids":["27653213"],"is_preprint":false},{"year":2015,"finding":"ZDHHC21 palmitoylates the α1D adrenoceptor and forms a molecular complex with it; loss of ZDHHC21 function (F233Δ mutation) diminishes α1 adrenergic receptor-dependent vascular tone, causing hypotension and tachycardia in vivo.","method":"Biochemical palmitoylation assay, co-immunoprecipitation, isolated vessel contractility studies, in vivo phenylephrine infusion, telemetry in F233Δ mice","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical interaction assay plus in vitro palmitoylation assay plus in vivo functional phenotype in a loss-of-function mouse; multiple orthogonal methods in a single study","pmids":["26715683"],"is_preprint":false},{"year":2021,"finding":"DHHC21 is a Ca²⁺/calmodulin-dependent palmitoyl acyltransferase; disruption of its Ca²⁺/calmodulin-binding domain prevents S-acylation of proximal TCR signaling proteins, blocking activation and differentiation of naïve CD4⁺ T cells into Th1, Th2, and Th17 lineages without affecting thymic development.","method":"Zdhhc21dep mice (calmodulin-binding domain disruption), T cell S-acylation assays, T cell activation and differentiation assays in vitro and in vivo","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function mouse model with specific domain disruption plus multiple orthogonal cellular assays (S-acylation, activation markers, lineage differentiation)","pmids":["34080635"],"is_preprint":false},{"year":2020,"finding":"DHHC21 mediates S-acylation of key TCR signaling proteins; loss of DHHC21 disrupts early TCR signaling events and suppresses T cell activation markers and differentiation into effector subtypes.","method":"DHHC21 knockdown, S-acylation assay of TCR signaling proteins, T cell activation and differentiation assays","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, knockdown with functional readouts of S-acylation and T cell activation, but no rescue or structural validation","pmids":["32789573"],"is_preprint":false},{"year":2017,"finding":"ZDHHC21 mediates gut epithelial barrier hyperpermeability in response to TNF-α/IFN-γ; ZDHHC21-deficient mice and pharmacological PAT inhibition both attenuate intestinal barrier dysfunction and villus damage after thermal injury.","method":"ZDHHC21-deficient mice, pharmacological inhibition (2-bromopalmitate), ECIS permeability assay, FITC-dextran permeability assay, acyl-biotin exchange assay, histology and electron microscopy","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological loss-of-function with multiple permeability readouts; mechanism inferred but specific substrate not identified","pmids":["28838985"],"is_preprint":false},{"year":2021,"finding":"DHHC21 promotes α1-adrenergic receptor (α1AR) palmitoylation and downstream ERK activation in renal vasculature during sepsis; DHHC21-deficient mice show blunted α1AR-dependent vasoconstriction and better-preserved renal perfusion after cecal ligation and puncture.","method":"Zdhhc21dep/dep mice, CLP sepsis model, palmitoylation assay (α1AR), ERK phosphorylation assay, renal blood flow measurement, isolated vessel contractility","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function plus biochemical palmitoylation and signaling assays plus in vivo hemodynamic measurements; single lab","pmids":["34045489"],"is_preprint":false},{"year":2023,"finding":"ZDHHC21 specifically catalyzes palmitoylation of mitochondrial adenylate kinase 2 (AK2), activating mitochondrial OXPHOS in AML cells; ZDHHC21 inhibition/depletion reduces AK2 palmitoylation and OXPHOS activity, inducing myeloid differentiation and reducing stemness.","method":"ZDHHC21 depletion/inhibition, palmitoylation assay (AK2), OXPHOS measurement, myeloid differentiation assays, in vivo AML xenograft model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological loss-of-function with identification of specific substrate (AK2) and downstream functional consequence (OXPHOS), validated in vitro and in vivo in multiple AML models","pmids":["37216691"],"is_preprint":false},{"year":2024,"finding":"ZDHHC21 interacts with FASN and palmitoylates it at Cys1317, decreasing FASN protein stability and fatty acid synthesis, thereby suppressing DLBCL cell proliferation.","method":"Co-immunoprecipitation, palmitoylation assay, site-directed mutagenesis (Cys1317), in vitro and in vivo DLBCL proliferation assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — specific palmitoylation site identified by mutagenesis, co-IP for interaction, functional readout of protein stability and proliferation in vitro and in vivo; single lab","pmids":["38195819"],"is_preprint":false},{"year":2023,"finding":"A gain-of-function ZDHHC21 missense mutation (p.T209S) identified in a familial AD pedigree enhances palmitoylation of FYN tyrosine kinase and APP; increased FYN palmitoylation causes NMDAR2B overactivation and excitotoxicity leading to synaptic dysfunction and neuronal loss. Increased APP palmitoylation contributes to Aβ production. Palmitoyltransferase inhibitors reversed synaptic dysfunction in knock-in mice.","method":"Exome sequencing, CRISPR/Cas9 knock-in mouse (ZDHHC21T209S), palmitoylation assays (FYN, APP), LTP field recordings, Morris water maze, ELISA for Aβ, electron microscopy, Golgi staining, pharmacological inhibition","journal":"BMC medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — knock-in mouse model with gain-of-function mutation, multiple orthogonal biochemical and functional readouts identifying specific substrates (FYN, APP) and downstream pathway; pharmacological rescue validates mechanism","pmids":["37365538"],"is_preprint":false},{"year":2025,"finding":"ZDHHC21 is a Ca²⁺-activated S-acyltransferase for STIM1; upon ER Ca²⁺ store depletion, plasma membrane-localized DHHC21 is recruited into Orai1/STIM1 puncta where it physically binds STIM1 and catalyzes its S-acylation, which is required for store-operated calcium entry (SOCE). Depilated mice lacking Ca²⁺-dependent DHHC21 activation show impaired STIM1 S-acylation and SOCE, and phenocopy autoimmune lymphoproliferative syndrome (ALPS).","method":"Depilated mouse model (Ca²⁺/calmodulin-binding domain disruption), STIM1 S-acylation assay, live-cell imaging of DHHC21 recruitment into Orai1/STIM1 puncta, co-immunoprecipitation (DHHC21-STIM1), SOCE measurement in vitro and in vivo, immune phenotyping","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function mouse model plus co-IP plus dynamic live-cell localization plus S-acylation assay plus calcium entry functional readout; multiple orthogonal methods in a single study","pmids":["41279060"],"is_preprint":true},{"year":2025,"finding":"AUF1 suppresses ZDHHC21 expression by promoting decay of ETS2 mRNA; ETS2 directly activates ZDHHC21 transcription. ZDHHC21 mediates palmitoylation of STING, which drives pyroptosis in lung epithelial cells during sepsis-induced ALI; knockdown of ZDHHC21 reduces STING palmitoylation and pyroptosis markers.","method":"RNA immunoprecipitation (RIP), RNA pulldown, mRNA decay assay (actinomycin D), ZDHHC21 knockdown/overexpression, STING palmitoylation assay, pyroptosis marker measurement (c-Caspase-1, GSDMD-N, IL-18, IL-1β), CLP and LPS in vivo/in vitro models","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple methods including RIP, palmitoylation assay, and functional pyroptosis assays; single lab, mechanism partially established through loss-of-function","pmids":["41460311"],"is_preprint":false}],"current_model":"ZDHHC21 is a plasma membrane-localized, Ca²⁺/calmodulin-activated palmitoyl acyltransferase (PAT) that S-acylates multiple substrates—including PLCβ1, α1D-adrenoceptor, FYN, APP, AK2, FASN, STIM1, and STING—to regulate endothelial barrier integrity, vascular tone, T cell receptor signaling and immune activation, store-operated calcium entry, mitochondrial OXPHOS, and inflammatory pyroptosis; its catalytic activity depends on Ca²⁺/calmodulin binding, and gain- or loss-of-function mutations in ZDHHC21 cause diverse pathologies ranging from vascular dysfunction and immunodeficiency to Alzheimer's disease and leukemia."},"narrative":{"mechanistic_narrative":"ZDHHC21 is a plasma membrane palmitoyl acyltransferase (PAT) that S-acylates a defined set of substrates to control vascular, immune, metabolic, and neuronal signaling [PMID:27653213, PMID:34080635]. Its catalytic activity is gated by Ca²⁺/calmodulin binding: disruption of the calmodulin-binding domain abolishes S-acylation of proximal T-cell receptor signaling proteins and blocks naïve CD4⁺ T-cell activation and Th1/Th2/Th17 differentiation without affecting thymic development [PMID:34080635, PMID:32789573]. In the vasculature, ZDHHC21 palmitoylates PLCβ1 to drive inflammation-induced endothelial barrier hyperpermeability and ICAM-1 expression [PMID:27653213], and forms a complex with and palmitoylates the α1D-adrenoceptor to sustain α1-adrenergic vasoconstriction and downstream ERK activation, controlling vascular tone and renal perfusion [PMID:26715683, PMID:34045489]. The same enzyme governs epithelial barrier integrity in response to TNF-α/IFN-γ [PMID:28838985]. Through substrate-specific acylation it also regulates store-operated calcium entry by being recruited into Orai1/STIM1 puncta upon ER store depletion, where it binds and S-acylates STIM1 [PMID:41279060], promotes mitochondrial OXPHOS by palmitoylating adenylate kinase 2 (AK2) [PMID:37216691], and palmitoylates STING to drive pyroptosis [PMID:41460311]. ZDHHC21 acylation activity is disease-linked: a gain-of-function p.T209S mutation in a familial Alzheimer's disease pedigree enhances palmitoylation of FYN and APP, causing NMDAR2B-mediated excitotoxicity and increased Aβ production, with palmitoyltransferase inhibitors reversing synaptic dysfunction in knock-in mice [PMID:37365538]. In cancer, ZDHHC21 supports AML stemness via AK2/OXPHOS [PMID:37216691] and palmitoylates FASN at Cys1317 to destabilize it and suppress DLBCL proliferation [PMID:38195819].","teleology":[{"year":2015,"claim":"Established that ZDHHC21 acts on a G-protein-coupled receptor by palmitoylating the α1D-adrenoceptor, linking the enzyme to control of vascular tone in vivo.","evidence":"Biochemical palmitoylation and co-IP plus isolated vessel contractility and telemetry in F233Δ loss-of-function mice","pmids":["26715683"],"confidence":"High","gaps":["Did not map the palmitoylated cysteine on the receptor","Did not establish whether Ca²⁺/calmodulin gates this particular reaction"]},{"year":2016,"claim":"Identified PLCβ1 as a vascular substrate placing ZDHHC21 acylation upstream of inflammation-induced endothelial hyperpermeability.","evidence":"Zdhhc21dep/dep mice with overexpression rescue using wild-type vs catalytic-mutant constructs, palmitoylation and permeability assays in vitro and in vivo","pmids":["27653213"],"confidence":"High","gaps":["Palmitoylation site on PLCβ1 not defined","Upstream signal coupling inflammation to enzyme activity not resolved"]},{"year":2017,"claim":"Extended ZDHHC21's barrier role to gut epithelium under inflammatory stress, showing genetic and pharmacological loss attenuate hyperpermeability.","evidence":"ZDHHC21-deficient mice and 2-bromopalmitate inhibition with ECIS/FITC-dextran permeability, acyl-biotin exchange, histology and EM after thermal injury","pmids":["28838985"],"confidence":"Medium","gaps":["Specific epithelial substrate not identified","2-bromopalmitate is not ZDHHC21-selective"]},{"year":2020,"claim":"First linked ZDHHC21 to immune signaling by showing it S-acylates proximal TCR signaling proteins required for T-cell activation.","evidence":"DHHC21 knockdown with S-acylation assays and T-cell activation/differentiation readouts","pmids":["32789573"],"confidence":"Medium","gaps":["No rescue or structural validation","Individual TCR substrates and their acylation sites not fully resolved"]},{"year":2021,"claim":"Defined ZDHHC21 as a Ca²⁺/calmodulin-dependent PAT, mechanistically coupling its catalytic activity to a regulatory domain and confirming its requirement for CD4⁺ T-cell lineage differentiation.","evidence":"Zdhhc21dep mice with calmodulin-binding domain disruption plus T-cell S-acylation, activation, and differentiation assays in vitro and in vivo","pmids":["34080635"],"confidence":"High","gaps":["Structural basis of calmodulin-mediated activation not solved","Which TCR-pathway substrates are directly versus indirectly affected unclear"]},{"year":2021,"claim":"Showed the α1-adrenergic axis controlled by ZDHHC21 operates during sepsis, coupling receptor palmitoylation to ERK activation and renal perfusion.","evidence":"Zdhhc21dep/dep mice in a CLP sepsis model with α1AR palmitoylation, ERK phosphorylation, renal blood flow, and vessel contractility measures","pmids":["34045489"],"confidence":"Medium","gaps":["Single lab","Direct versus indirect contribution of receptor acylation to ERK output not separated"]},{"year":2023,"claim":"Connected ZDHHC21 to mitochondrial metabolism in cancer by identifying AK2 as a substrate whose palmitoylation sustains OXPHOS and AML stemness.","evidence":"ZDHHC21 depletion/inhibition with AK2 palmitoylation, OXPHOS measurement, myeloid differentiation assays, and in vivo AML xenografts","pmids":["37216691"],"confidence":"High","gaps":["AK2 palmitoylation site not mapped","How a plasma membrane PAT accesses a mitochondrial substrate not explained"]},{"year":2023,"claim":"Provided direct disease causation by showing a gain-of-function ZDHHC21 mutation enhances FYN and APP palmitoylation to produce Alzheimer's pathology rescuable by PAT inhibitors.","evidence":"Exome sequencing of a familial AD pedigree plus CRISPR knock-in mice with FYN/APP palmitoylation assays, LTP recordings, behavior, Aβ ELISA, and pharmacological rescue","pmids":["37365538"],"confidence":"High","gaps":["How p.T209S alters enzyme activity at the molecular level not defined","Relative contributions of FYN versus APP acylation to phenotype not dissected"]},{"year":2024,"claim":"Showed substrate acylation can be destabilizing, with ZDHHC21 palmitoylating FASN at Cys1317 to reduce its stability and suppress lymphoma proliferation.","evidence":"Co-IP, palmitoylation assay, Cys1317 site-directed mutagenesis, and DLBCL proliferation assays in vitro and in vivo","pmids":["38195819"],"confidence":"High","gaps":["Mechanism by which acylation destabilizes FASN not detailed","Context determining tumor-suppressive versus tumor-supportive ZDHHC21 roles unclear"]},{"year":2025,"claim":"Resolved how Ca²⁺ gating is deployed spatially, showing store depletion recruits ZDHHC21 into Orai1/STIM1 puncta where it binds and S-acylates STIM1 to enable SOCE.","evidence":"Depilated mouse model with calmodulin-binding domain disruption plus STIM1 S-acylation, live-cell puncta imaging, co-IP, SOCE measurement, and immune phenotyping (preprint)","pmids":["41279060"],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","STIM1 acylation site and how acylation promotes SOCE not fully defined"]},{"year":2025,"claim":"Placed ZDHHC21 in an AUF1–ETS2 transcriptional circuit and identified STING palmitoylation as a driver of epithelial pyroptosis in sepsis-induced lung injury.","evidence":"RIP, RNA pulldown, mRNA decay assays, ZDHHC21 knockdown/overexpression, STING palmitoylation and pyroptosis marker assays in CLP/LPS models","pmids":["41460311"],"confidence":"Medium","gaps":["Single lab","STING palmitoylation site not mapped","Direct versus indirect effect on pyroptosis not separated"]},{"year":null,"claim":"A unifying structural and regulatory model explaining how Ca²⁺/calmodulin gating selects among diverse substrates across plasma membrane, ER-PM junctions, and mitochondria remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of ZDHHC21 or its calmodulin-bound active state","Rules governing substrate selectivity unknown","How a plasma-membrane PAT acts on mitochondrial substrates like AK2 is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,6,7,8,9,10]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6,7,8]}],"complexes":[],"partners":["PLCB1","ADRA1D","FYN","APP","AK2","FASN","STIM1","STING1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IVQ6","full_name":"Palmitoyltransferase ZDHHC21","aliases":["DHHC domain-containing cysteine-rich protein 21","DHHC-21","Zinc finger DHHC domain-containing protein 21"],"length_aa":265,"mass_kda":31.4,"function":"Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates (PubMed:22031296). Palmitoylates sex steroid hormone receptors, including ESR1, PGR and AR, thereby regulating their targeting to the plasma membrane (PubMed:22031296). This affects rapid intracellular signaling by sex hormones via ERK and AKT kinases and the generation of cAMP, but does not affect that mediated by their nuclear receptor (PubMed:22031296). Palmitoylates FYN, regulates its localization in hair follicles and plays a key role in epidermal homeostasis and hair follicle differentiation. Through the palmitoylation of PLCB1 and the regulation of PLCB1 downstream signaling may indirectly regulate the function of the endothelial barrier and the adhesion of leukocytes to the endothelium. Also has a palmitoyltransferase activity toward ADRA1D, positively regulating its activity and expression and may thereby play a role in vascular contraction. May also palmitoylate eNOS and LCK (By similarity)","subcellular_location":"Golgi apparatus membrane; Golgi apparatus, cis-Golgi network membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IVQ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC21","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZDHHC21","total_profiled":1310},"omim":[{"mim_id":"614605","title":"ZDHHC PALMITOYLTRANSFERASE 21; ZDHHC21","url":"https://www.omim.org/entry/614605"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC21"},"hgnc":{"alias_symbol":["HSPC097","DNZ1","DHHC21"],"prev_symbol":[]},"alphafold":{"accession":"Q8IVQ6","domains":[{"cath_id":"1.20.140","chopping":"10-71_131-159_171-244","consensus_level":"high","plddt":91.325,"start":10,"end":244}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVQ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVQ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IVQ6-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC21","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC21"},"sequence":{"accession":"Q8IVQ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IVQ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IVQ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IVQ6"}},"corpus_meta":[{"pmid":"27653213","id":"PMC_27653213","title":"Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27653213","citation_count":61,"is_preprint":false},{"pmid":"37216691","id":"PMC_37216691","title":"The palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce differentiation block and stemness in AML.","date":"2023","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/37216691","citation_count":48,"is_preprint":false},{"pmid":"38195819","id":"PMC_38195819","title":"Targeting ZDHHC21/FASN axis for the treatment of diffuse large B-cell lymphoma.","date":"2024","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/38195819","citation_count":33,"is_preprint":false},{"pmid":"37365538","id":"PMC_37365538","title":"Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer's disease.","date":"2023","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37365538","citation_count":29,"is_preprint":false},{"pmid":"26715683","id":"PMC_26715683","title":"The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.","date":"2015","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26715683","citation_count":23,"is_preprint":false},{"pmid":"34080635","id":"PMC_34080635","title":"Ca2+-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34080635","citation_count":21,"is_preprint":false},{"pmid":"32789573","id":"PMC_32789573","title":"Regulation of T cell receptor signaling by protein acyltransferase DHHC21.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32789573","citation_count":20,"is_preprint":false},{"pmid":"28838985","id":"PMC_28838985","title":"Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation.","date":"2017","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28838985","citation_count":14,"is_preprint":false},{"pmid":"34045489","id":"PMC_34045489","title":"DHHC21 deficiency attenuates renal dysfunction during septic injury.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34045489","citation_count":13,"is_preprint":false},{"pmid":"41460311","id":"PMC_41460311","title":"Sepsis-induced acute lung injury: AUF1 regulates pyroptosis via ETS2/ZDHHC21-mediated STING palmitoylation : A therapeutic target for lung injury.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41460311","citation_count":1,"is_preprint":false},{"pmid":"41279060","id":"PMC_41279060","title":"DHHC21 is a STIM1 protein S-acyltransferase that modulates immune function in vivo.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279060","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.09.681383","title":"DHHC21 is a STIM1 protein S-acyltransferase that modulates immune function  <i>in vivo</i>","date":"2025-10-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.09.681383","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8859,"output_tokens":3265,"usd":0.037776,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10756,"output_tokens":3971,"usd":0.076527,"stage2_stop_reason":"end_turn"},"total_usd":0.114303,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"DHHC21 palmitoylates PLCβ1 in vascular endothelial cells; inflammation enhances PLCβ1 palmitoylation and signaling activity, effects significantly reduced in Zdhhc21dep/dep mice and rescued by DHHC21 overexpression. Overexpression of wild-type but not catalytically mutant PLCβ1 augmented barrier dysfunction, placing DHHC21-mediated PLCβ1 palmitoylation upstream of endothelial junction hyperpermeability and ICAM-1 expression.\",\n      \"method\": \"Zdhhc21dep/dep mice (loss-of-function), DHHC21 overexpression rescue, palmitoylation assay, endothelial permeability assay, leukocyte adhesion assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function mouse model plus overexpression rescue with wild-type vs. mutant constructs across multiple orthogonal functional readouts, replicated in vitro and in vivo\",\n      \"pmids\": [\"27653213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZDHHC21 palmitoylates the α1D adrenoceptor and forms a molecular complex with it; loss of ZDHHC21 function (F233Δ mutation) diminishes α1 adrenergic receptor-dependent vascular tone, causing hypotension and tachycardia in vivo.\",\n      \"method\": \"Biochemical palmitoylation assay, co-immunoprecipitation, isolated vessel contractility studies, in vivo phenylephrine infusion, telemetry in F233Δ mice\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical interaction assay plus in vitro palmitoylation assay plus in vivo functional phenotype in a loss-of-function mouse; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"26715683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DHHC21 is a Ca²⁺/calmodulin-dependent palmitoyl acyltransferase; disruption of its Ca²⁺/calmodulin-binding domain prevents S-acylation of proximal TCR signaling proteins, blocking activation and differentiation of naïve CD4⁺ T cells into Th1, Th2, and Th17 lineages without affecting thymic development.\",\n      \"method\": \"Zdhhc21dep mice (calmodulin-binding domain disruption), T cell S-acylation assays, T cell activation and differentiation assays in vitro and in vivo\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function mouse model with specific domain disruption plus multiple orthogonal cellular assays (S-acylation, activation markers, lineage differentiation)\",\n      \"pmids\": [\"34080635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DHHC21 mediates S-acylation of key TCR signaling proteins; loss of DHHC21 disrupts early TCR signaling events and suppresses T cell activation markers and differentiation into effector subtypes.\",\n      \"method\": \"DHHC21 knockdown, S-acylation assay of TCR signaling proteins, T cell activation and differentiation assays\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, knockdown with functional readouts of S-acylation and T cell activation, but no rescue or structural validation\",\n      \"pmids\": [\"32789573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZDHHC21 mediates gut epithelial barrier hyperpermeability in response to TNF-α/IFN-γ; ZDHHC21-deficient mice and pharmacological PAT inhibition both attenuate intestinal barrier dysfunction and villus damage after thermal injury.\",\n      \"method\": \"ZDHHC21-deficient mice, pharmacological inhibition (2-bromopalmitate), ECIS permeability assay, FITC-dextran permeability assay, acyl-biotin exchange assay, histology and electron microscopy\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological loss-of-function with multiple permeability readouts; mechanism inferred but specific substrate not identified\",\n      \"pmids\": [\"28838985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DHHC21 promotes α1-adrenergic receptor (α1AR) palmitoylation and downstream ERK activation in renal vasculature during sepsis; DHHC21-deficient mice show blunted α1AR-dependent vasoconstriction and better-preserved renal perfusion after cecal ligation and puncture.\",\n      \"method\": \"Zdhhc21dep/dep mice, CLP sepsis model, palmitoylation assay (α1AR), ERK phosphorylation assay, renal blood flow measurement, isolated vessel contractility\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function plus biochemical palmitoylation and signaling assays plus in vivo hemodynamic measurements; single lab\",\n      \"pmids\": [\"34045489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC21 specifically catalyzes palmitoylation of mitochondrial adenylate kinase 2 (AK2), activating mitochondrial OXPHOS in AML cells; ZDHHC21 inhibition/depletion reduces AK2 palmitoylation and OXPHOS activity, inducing myeloid differentiation and reducing stemness.\",\n      \"method\": \"ZDHHC21 depletion/inhibition, palmitoylation assay (AK2), OXPHOS measurement, myeloid differentiation assays, in vivo AML xenograft model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological loss-of-function with identification of specific substrate (AK2) and downstream functional consequence (OXPHOS), validated in vitro and in vivo in multiple AML models\",\n      \"pmids\": [\"37216691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC21 interacts with FASN and palmitoylates it at Cys1317, decreasing FASN protein stability and fatty acid synthesis, thereby suppressing DLBCL cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, palmitoylation assay, site-directed mutagenesis (Cys1317), in vitro and in vivo DLBCL proliferation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — specific palmitoylation site identified by mutagenesis, co-IP for interaction, functional readout of protein stability and proliferation in vitro and in vivo; single lab\",\n      \"pmids\": [\"38195819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A gain-of-function ZDHHC21 missense mutation (p.T209S) identified in a familial AD pedigree enhances palmitoylation of FYN tyrosine kinase and APP; increased FYN palmitoylation causes NMDAR2B overactivation and excitotoxicity leading to synaptic dysfunction and neuronal loss. Increased APP palmitoylation contributes to Aβ production. Palmitoyltransferase inhibitors reversed synaptic dysfunction in knock-in mice.\",\n      \"method\": \"Exome sequencing, CRISPR/Cas9 knock-in mouse (ZDHHC21T209S), palmitoylation assays (FYN, APP), LTP field recordings, Morris water maze, ELISA for Aβ, electron microscopy, Golgi staining, pharmacological inhibition\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — knock-in mouse model with gain-of-function mutation, multiple orthogonal biochemical and functional readouts identifying specific substrates (FYN, APP) and downstream pathway; pharmacological rescue validates mechanism\",\n      \"pmids\": [\"37365538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC21 is a Ca²⁺-activated S-acyltransferase for STIM1; upon ER Ca²⁺ store depletion, plasma membrane-localized DHHC21 is recruited into Orai1/STIM1 puncta where it physically binds STIM1 and catalyzes its S-acylation, which is required for store-operated calcium entry (SOCE). Depilated mice lacking Ca²⁺-dependent DHHC21 activation show impaired STIM1 S-acylation and SOCE, and phenocopy autoimmune lymphoproliferative syndrome (ALPS).\",\n      \"method\": \"Depilated mouse model (Ca²⁺/calmodulin-binding domain disruption), STIM1 S-acylation assay, live-cell imaging of DHHC21 recruitment into Orai1/STIM1 puncta, co-immunoprecipitation (DHHC21-STIM1), SOCE measurement in vitro and in vivo, immune phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function mouse model plus co-IP plus dynamic live-cell localization plus S-acylation assay plus calcium entry functional readout; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"41279060\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AUF1 suppresses ZDHHC21 expression by promoting decay of ETS2 mRNA; ETS2 directly activates ZDHHC21 transcription. ZDHHC21 mediates palmitoylation of STING, which drives pyroptosis in lung epithelial cells during sepsis-induced ALI; knockdown of ZDHHC21 reduces STING palmitoylation and pyroptosis markers.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pulldown, mRNA decay assay (actinomycin D), ZDHHC21 knockdown/overexpression, STING palmitoylation assay, pyroptosis marker measurement (c-Caspase-1, GSDMD-N, IL-18, IL-1β), CLP and LPS in vivo/in vitro models\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple methods including RIP, palmitoylation assay, and functional pyroptosis assays; single lab, mechanism partially established through loss-of-function\",\n      \"pmids\": [\"41460311\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZDHHC21 is a plasma membrane-localized, Ca²⁺/calmodulin-activated palmitoyl acyltransferase (PAT) that S-acylates multiple substrates—including PLCβ1, α1D-adrenoceptor, FYN, APP, AK2, FASN, STIM1, and STING—to regulate endothelial barrier integrity, vascular tone, T cell receptor signaling and immune activation, store-operated calcium entry, mitochondrial OXPHOS, and inflammatory pyroptosis; its catalytic activity depends on Ca²⁺/calmodulin binding, and gain- or loss-of-function mutations in ZDHHC21 cause diverse pathologies ranging from vascular dysfunction and immunodeficiency to Alzheimer's disease and leukemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC21 is a plasma membrane palmitoyl acyltransferase (PAT) that S-acylates a defined set of substrates to control vascular, immune, metabolic, and neuronal signaling [#0, #2]. Its catalytic activity is gated by Ca²⁺/calmodulin binding: disruption of the calmodulin-binding domain abolishes S-acylation of proximal T-cell receptor signaling proteins and blocks naïve CD4⁺ T-cell activation and Th1/Th2/Th17 differentiation without affecting thymic development [#2, #3]. In the vasculature, ZDHHC21 palmitoylates PLCβ1 to drive inflammation-induced endothelial barrier hyperpermeability and ICAM-1 expression [#0], and forms a complex with and palmitoylates the α1D-adrenoceptor to sustain α1-adrenergic vasoconstriction and downstream ERK activation, controlling vascular tone and renal perfusion [#1, #5]. The same enzyme governs epithelial barrier integrity in response to TNF-α/IFN-γ [#4]. Through substrate-specific acylation it also regulates store-operated calcium entry by being recruited into Orai1/STIM1 puncta upon ER store depletion, where it binds and S-acylates STIM1 [#9], promotes mitochondrial OXPHOS by palmitoylating adenylate kinase 2 (AK2) [#6], and palmitoylates STING to drive pyroptosis [#10]. ZDHHC21 acylation activity is disease-linked: a gain-of-function p.T209S mutation in a familial Alzheimer's disease pedigree enhances palmitoylation of FYN and APP, causing NMDAR2B-mediated excitotoxicity and increased Aβ production, with palmitoyltransferase inhibitors reversing synaptic dysfunction in knock-in mice [#8]. In cancer, ZDHHC21 supports AML stemness via AK2/OXPHOS [#6] and palmitoylates FASN at Cys1317 to destabilize it and suppress DLBCL proliferation [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that ZDHHC21 acts on a G-protein-coupled receptor by palmitoylating the α1D-adrenoceptor, linking the enzyme to control of vascular tone in vivo.\",\n      \"evidence\": \"Biochemical palmitoylation and co-IP plus isolated vessel contractility and telemetry in F233Δ loss-of-function mice\",\n      \"pmids\": [\"26715683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the palmitoylated cysteine on the receptor\", \"Did not establish whether Ca²⁺/calmodulin gates this particular reaction\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PLCβ1 as a vascular substrate placing ZDHHC21 acylation upstream of inflammation-induced endothelial hyperpermeability.\",\n      \"evidence\": \"Zdhhc21dep/dep mice with overexpression rescue using wild-type vs catalytic-mutant constructs, palmitoylation and permeability assays in vitro and in vivo\",\n      \"pmids\": [\"27653213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Palmitoylation site on PLCβ1 not defined\", \"Upstream signal coupling inflammation to enzyme activity not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended ZDHHC21's barrier role to gut epithelium under inflammatory stress, showing genetic and pharmacological loss attenuate hyperpermeability.\",\n      \"evidence\": \"ZDHHC21-deficient mice and 2-bromopalmitate inhibition with ECIS/FITC-dextran permeability, acyl-biotin exchange, histology and EM after thermal injury\",\n      \"pmids\": [\"28838985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific epithelial substrate not identified\", \"2-bromopalmitate is not ZDHHC21-selective\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"First linked ZDHHC21 to immune signaling by showing it S-acylates proximal TCR signaling proteins required for T-cell activation.\",\n      \"evidence\": \"DHHC21 knockdown with S-acylation assays and T-cell activation/differentiation readouts\",\n      \"pmids\": [\"32789573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue or structural validation\", \"Individual TCR substrates and their acylation sites not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ZDHHC21 as a Ca²⁺/calmodulin-dependent PAT, mechanistically coupling its catalytic activity to a regulatory domain and confirming its requirement for CD4⁺ T-cell lineage differentiation.\",\n      \"evidence\": \"Zdhhc21dep mice with calmodulin-binding domain disruption plus T-cell S-acylation, activation, and differentiation assays in vitro and in vivo\",\n      \"pmids\": [\"34080635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of calmodulin-mediated activation not solved\", \"Which TCR-pathway substrates are directly versus indirectly affected unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the α1-adrenergic axis controlled by ZDHHC21 operates during sepsis, coupling receptor palmitoylation to ERK activation and renal perfusion.\",\n      \"evidence\": \"Zdhhc21dep/dep mice in a CLP sepsis model with α1AR palmitoylation, ERK phosphorylation, renal blood flow, and vessel contractility measures\",\n      \"pmids\": [\"34045489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus indirect contribution of receptor acylation to ERK output not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected ZDHHC21 to mitochondrial metabolism in cancer by identifying AK2 as a substrate whose palmitoylation sustains OXPHOS and AML stemness.\",\n      \"evidence\": \"ZDHHC21 depletion/inhibition with AK2 palmitoylation, OXPHOS measurement, myeloid differentiation assays, and in vivo AML xenografts\",\n      \"pmids\": [\"37216691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"AK2 palmitoylation site not mapped\", \"How a plasma membrane PAT accesses a mitochondrial substrate not explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided direct disease causation by showing a gain-of-function ZDHHC21 mutation enhances FYN and APP palmitoylation to produce Alzheimer's pathology rescuable by PAT inhibitors.\",\n      \"evidence\": \"Exome sequencing of a familial AD pedigree plus CRISPR knock-in mice with FYN/APP palmitoylation assays, LTP recordings, behavior, Aβ ELISA, and pharmacological rescue\",\n      \"pmids\": [\"37365538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p.T209S alters enzyme activity at the molecular level not defined\", \"Relative contributions of FYN versus APP acylation to phenotype not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed substrate acylation can be destabilizing, with ZDHHC21 palmitoylating FASN at Cys1317 to reduce its stability and suppress lymphoma proliferation.\",\n      \"evidence\": \"Co-IP, palmitoylation assay, Cys1317 site-directed mutagenesis, and DLBCL proliferation assays in vitro and in vivo\",\n      \"pmids\": [\"38195819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which acylation destabilizes FASN not detailed\", \"Context determining tumor-suppressive versus tumor-supportive ZDHHC21 roles unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved how Ca²⁺ gating is deployed spatially, showing store depletion recruits ZDHHC21 into Orai1/STIM1 puncta where it binds and S-acylates STIM1 to enable SOCE.\",\n      \"evidence\": \"Depilated mouse model with calmodulin-binding domain disruption plus STIM1 S-acylation, live-cell puncta imaging, co-IP, SOCE measurement, and immune phenotyping (preprint)\",\n      \"pmids\": [\"41279060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"STIM1 acylation site and how acylation promotes SOCE not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ZDHHC21 in an AUF1–ETS2 transcriptional circuit and identified STING palmitoylation as a driver of epithelial pyroptosis in sepsis-induced lung injury.\",\n      \"evidence\": \"RIP, RNA pulldown, mRNA decay assays, ZDHHC21 knockdown/overexpression, STING palmitoylation and pyroptosis marker assays in CLP/LPS models\",\n      \"pmids\": [\"41460311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"STING palmitoylation site not mapped\", \"Direct versus indirect effect on pyroptosis not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and regulatory model explaining how Ca²⁺/calmodulin gating selects among diverse substrates across plasma membrane, ER-PM junctions, and mitochondria remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of ZDHHC21 or its calmodulin-bound active state\", \"Rules governing substrate selectivity unknown\", \"How a plasma-membrane PAT acts on mitochondrial substrates like AK2 is unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7, 8, 9, 10]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLCB1\", \"ADRA1D\", \"FYN\", \"APP\", \"AK2\", \"FASN\", \"STIM1\", \"STING1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}