{"gene":"PSTPIP2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2005,"finding":"PSTPIP2 directly bundles F-actin in vitro, and its overexpression in macrophages decreases CSF-1-induced membrane ruffling while increasing filopodia formation, motility, and CSF-1-mediated chemotaxis; PSTPIP2 colocalizes with cortical and filopodial F-actin in vivo.","method":"In vitro F-actin bundling assay with purified MAYP/PSTPIP2; overexpression and RNAi knockdown in macrophages with actin phenotype readouts; fluorescence microscopy colocalization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of F-actin bundling plus loss- and gain-of-function cellular assays with defined actin phenotypes","pmids":["15788569"],"is_preprint":false},{"year":2005,"finding":"A missense mutation (L98P) in Pstpip2 is the causative genetic lesion for the cmo (chronic multifocal osteomyelitis) mouse autoinflammatory disorder; the L98P mutation results in loss of detectable PSTPIP2 protein in macrophages, mast cells, and osteoclasts.","method":"Positional cloning, direct sequencing, backcross mapping to a 1.3 Mb interval on murine chromosome 18","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 — positional cloning with direct sequencing replicated across independent labs","pmids":["16122996"],"is_preprint":false},{"year":2006,"finding":"A second Pstpip2 missense mutation (I282N, Lupo) causes protein instability and reduces PSTPIP2 expression ~3-fold in macrophages; the autoinflammatory disease is transferable by bone marrow transplantation and develops in the absence of lymphocytes, implicating macrophages as the key effector cell.","method":"Positional cloning of ENU-induced mutation; bone marrow transplantation; clodronate liposome macrophage depletion; in vitro cytokine measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — positional cloning plus bone marrow transplant epistasis plus macrophage depletion rescue","pmids":["16397132"],"is_preprint":false},{"year":2009,"finding":"PSTPIP2 deficiency causes expansion of macrophage progenitors and increased CSF-1R-dependent ERK1/2 phosphorylation and proliferation in macrophages; retroviral restoration of wild-type PSTPIP2 normalizes aberrant MIP-1α and IL-6 production, placing PSTPIP2 as a negative feedback regulator of CSF-1R signaling.","method":"Bone marrow transplantation; retroviral PSTPIP2 rescue; flow cytometry of progenitor populations; intracellular signaling (pERK1/2); cytokine ELISA","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including retroviral rescue and signaling readouts in primary cells","pmids":["19608749"],"is_preprint":false},{"year":2012,"finding":"PSTPIP2 suppresses osteoclast development: tyrosine phosphorylation of PSTPIP2 and a functional F-BAR domain are essential for inhibiting TRAP expression and osteoclast precursor fusion, while interaction with PEST-type phosphatases is only required for suppression of TRAP expression. PSTPIP2 deficiency elevates CSF-1R-dependent MIP-1α production, driving osteoclastogenesis.","method":"In vitro osteoclastogenesis assay with purified precursors from cmo and Lupo mice; structure-function mutagenesis (F-BAR domain mutants, phosphorylation site mutants, W232A PEST-binding mutant); PLX3397 CSF-1R/c-Kit inhibitor treatment in vivo","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — structure-function mutagenesis with defined cellular phenotypes and in vivo pharmacological rescue","pmids":["22923495"],"is_preprint":false},{"year":2014,"finding":"IL-1β (but not IL-1α) drives cmo autoinflammatory disease via an inflammasome-independent, caspase-1-independent pathway; neutrophils (not macrophages) from cmo mice secrete excess IL-1β in response to ATP, silica, and Pseudomonas, and this response is blocked by serine protease inhibitors.","method":"Genetic epistasis (IL-1RI-deficient × cmo mice); IL-1α/β cytokine-specific knockout crosses; NLRP3 and caspase-1 knockout crosses; neutrophil-specific IL-1β secretion assay with serine protease inhibitor treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic epistasis crosses with defined pathway placement and pharmacological validation","pmids":["24395802"],"is_preprint":false},{"year":2014,"finding":"PSTPIP2 is a GATA-1-repressed gene in megakaryocytes; overexpression impairs megakaryocytic differentiation and enhances activation of Src family kinases (specifically LYN) while reducing ERK phosphorylation. The W232A mutation that disrupts PEST phosphatase binding abolishes these effects, indicating that PSTPIP2 acts through PEST phosphatases to modulate CSK/LYN signaling.","method":"Ectopic expression and siRNA knockdown in K562 cells; dominant-negative and constitutively active LYN constructs; W232A PEST-binding mutant; phospho-signaling western blots; primary mouse bone marrow megakaryocyte differentiation assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function with structure-function mutagenesis and multiple orthogonal signaling readouts","pmids":["24407241"],"is_preprint":false},{"year":2015,"finding":"PSTPIP2 physically interacts with two inhibitory enzymes, SHIP1 and Csk. SHIP1 binds to the critical C-terminal tyrosine residues of PSTPIP2 that are essential for PEST-phosphatase-independent inhibitory function; disruption of this interaction enhances IL-1β processing in neutrophils. PSTPIP2 also binds Csk.","method":"Co-immunoprecipitation; mapping of SHIP1 binding to C-terminal PSTPIP2 tyrosines; SHIP1 pharmacological inhibition in neutrophils with IL-1β processing readout","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional validation via pharmacological inhibition in primary neutrophils","pmids":["26304991"],"is_preprint":false},{"year":2011,"finding":"PSTPIP2 localizes to detergent-resistant membranes (lipid rafts) containing the HCV RNA replication complex, and its membrane-deforming activity is required for HCV membranous web formation and replication; a PSTPIP2 mutant defective in membrane curvature induction fails to support HCV replication.","method":"RNAi knockdown in HCV replicon-harboring and HCV-infected cells; detergent-resistant membrane fractionation; membrane-curvature mutant complementation; HCV protein/RNA quantification","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function plus structure-function mutant with specific mechanistic readout, single lab","pmids":["22130530"],"is_preprint":false},{"year":2022,"finding":"In mice, disruption of the PEST-PTP binding site in PSTPIP2 causes symptomatic autoinflammatory disease, while disruption of the SHIP1 interaction site does not; both interactions contribute to control of IL-1β production in neutrophils, while PEST-PTPs uniquely regulate reactive oxygen species and CXCL2 chemokine production.","method":"Knock-in mouse strains with site-specific mutations disrupting PEST-PTP or SHIP1 binding sites; measurement of disease symptoms, IL-1β, ROS, and CXCL2 in primary neutrophils","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic separation-of-function experiments with multiple orthogonal inflammatory readouts","pmids":["36605205"],"is_preprint":false},{"year":2018,"finding":"PSTPIP2 hypermethylation by DNMT3a and DNMT3b at the 5'-UTR CpG region silences PSTPIP2 expression in LPS-stimulated macrophages; overexpression of PSTPIP2 inhibits M1 polarization by suppressing STAT1 activity and promotes M2 polarization by enhancing STAT6 activity.","method":"Reduced representation bisulfite sequencing (RRBS); ChIP for DNMT3a/3b; AAV9-PSTPIP2 overexpression in vivo; STAT1/STAT6 pathway analysis in RAW264.7 cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP validation of epigenetic mechanism plus pathway-level signaling readouts, single lab","pmids":["29993036"],"is_preprint":false},{"year":2022,"finding":"PSTPIP2 regulates synovial macrophage polarization and dynamics via estrogen receptor β (ERβ); PSTPIP2-high synovial macrophages form a tight immunological barrier in the joint lining layer, and this polarization effect is dependent on ERβ signaling.","method":"Pstpip2-Cre reporter mice; Esr2fl/fl/Adgre-Cre conditional knockout; AAV-mediated PSTPIP2 overexpression; macrophage dynamics and polarization assays in synovial tissue","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — conditional genetic knockouts with reporter mice, single lab","pmids":["36324152"],"is_preprint":false},{"year":2024,"finding":"PSTPIP2 regulates IL-19 production in damaged renal tubular epithelial cells via suppression of the NF-κB pathway; secreted IL-19 then drives neutrophil extracellular trap (NET) formation via the IL-20Rβ receptor, and NETs in turn promote renal tubular epithelial cell apoptosis.","method":"Conditional Pstpip2 knock-in mice; Ly6G neutralizing antibody neutrophil depletion; PAD4 inhibitor NET prevention; in vitro IL-19 neutralization and IL-20Rβ blocking; NF-κB pathway analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic and pharmacological epistasis plus in vitro pathway mapping, single lab","pmids":["38314821"],"is_preprint":false},{"year":2020,"finding":"H3K27ac-mediated histone acetylation at the PSTPIP2 promoter regulates its expression in renal tubular epithelial cells; HDAC inhibition upregulates PSTPIP2 and protects against cisplatin-induced apoptosis. PSTPIP2 overexpression inhibits apoptosis of renal tubular epithelial cells.","method":"ChIP assay for H3K27ac at PSTPIP2 promoter; AAV-PSTPIP2 overexpression in vivo; siRNA knockdown in vitro; TSA HDAC inhibitor treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP validation of epigenetic regulation plus in vivo/in vitro functional rescue, single lab","pmids":["33311489"],"is_preprint":false},{"year":2022,"finding":"DNMT3a directly binds to the Pstpip2 promoter (confirmed by ChIP) and acts as the principal epigenetic repressor of PSTPIP2 expression in alcohol-stimulated macrophages; PSTPIP2 suppresses alcohol-induced inflammation by regulating the STAT1 and NF-κB signaling pathways.","method":"ChIP assay for DNMT3a at Pstpip2 promoter; methylation-specific PCR; DNMT3a siRNA knockdown; STAT1 and NF-κB pathway analysis","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirmation of direct promoter binding plus signaling pathway readouts, single lab","pmids":["35149186"],"is_preprint":false},{"year":2024,"finding":"PSTPIP2 regulates caspase-8 activity in aristolochic acid nephropathy and its loss promotes PANoptosis (pyroptosis, apoptosis, and necroptosis) in renal tubular epithelial cells; HDAC1/HDAC2 suppress PSTPIP2 expression via histone deacetylation.","method":"Conditional Pstpip2 knock-in mice; HDAC1/HDAC2 inhibitor (romidepsin); caspase-8 activity measurement; PANoptosis markers in vivo and in vitro","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional genetic model plus pharmacological inhibition with specific caspase-8 mechanistic readout, single lab","pmids":["38073114"],"is_preprint":false},{"year":2018,"finding":"PSTPIP2 inhibits proliferation and inflammatory response of fibroblast-like synoviocytes via suppression of NF-κB signaling; overexpression reduces NF-κB pathway activity while knockdown promotes it.","method":"PSTPIP2 overexpression and siRNA knockdown in AIA rat FLS; NF-κB pathway western blot; proliferation and cytokine assays","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single cell type, no direct binding demonstration for NF-κB components","pmids":["30564127"],"is_preprint":false},{"year":2024,"finding":"PSTPIP2 protects against alcoholic liver injury by suppressing hepatocyte apoptosis via the STAT3 signaling pathway; STAT3 was identified as a direct downstream pathway regulated by PSTPIP2 in this context.","method":"AAV9-PSTPIP2 overexpression in EtOH-fed mice; stable lentiviral PSTPIP2-overexpressing AML-12 cells; caspase-dependent apoptosis markers; STAT3 pathway analysis","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 — gain-of-function with pathway readout but no direct binding or epistasis confirmation for STAT3, single lab","pmids":["38824967"],"is_preprint":false}],"current_model":"PSTPIP2 is an F-BAR/PCH domain adaptor protein expressed predominantly in myeloid cells that directly bundles F-actin to regulate macrophage filopodia formation and directional motility, and functions as a negative regulator of innate immune signaling by recruiting inhibitory partners PEST-family phosphatases, SHIP1, and Csk to dampen CSF-1R-dependent ERK signaling, Src family kinase (LYN) activity, NF-κB, and STAT1 pathways, thereby suppressing osteoclastogenesis, IL-1β processing by neutrophils, reactive oxygen species production, and inflammatory cytokine release; loss-of-function mutations cause autoinflammatory bone disease in mice through primed myeloid cells and excess IL-1β produced via serine protease-dependent, inflammasome-independent mechanisms."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing PSTPIP2 as a direct actin regulator resolved how an adaptor protein could reorganize the macrophage cortical cytoskeleton to control motility and membrane dynamics.","evidence":"In vitro F-actin bundling with purified PSTPIP2; overexpression/RNAi in macrophages with filopodia and chemotaxis readouts","pmids":["15788569"],"confidence":"High","gaps":["Whether actin bundling is separable from the signaling-adaptor function in vivo","Identity of upstream signals regulating PSTPIP2 actin-bundling activity"]},{"year":2005,"claim":"Positional cloning of two independent Pstpip2 loss-of-function mutations (L98P in cmo, I282N in Lupo) established that PSTPIP2 is essential for preventing autoinflammatory bone disease, and bone marrow transplant demonstrated a hematopoietic-intrinsic, macrophage-dependent mechanism.","evidence":"Positional cloning and sequencing of cmo and Lupo mice; bone marrow transplantation; macrophage depletion rescue","pmids":["16122996","16397132"],"confidence":"High","gaps":["Whether human PSTPIP2 mutations cause analogous disease","Which downstream inflammatory mediator drives bone pathology"]},{"year":2009,"claim":"Retroviral rescue experiments placed PSTPIP2 as a negative feedback regulator of CSF-1R signaling, explaining how its loss causes macrophage progenitor expansion and aberrant cytokine production via excessive ERK1/2 activation.","evidence":"Retroviral PSTPIP2 complementation in cmo bone marrow; pERK1/2 and cytokine ELISA in primary macrophages","pmids":["19608749"],"confidence":"High","gaps":["Direct physical interaction between PSTPIP2 and CSF-1R signaling components not yet mapped","Contribution of ERK-independent pathways"]},{"year":2012,"claim":"Structure-function dissection showed that the F-BAR domain and tyrosine phosphorylation of PSTPIP2 are independently required for suppressing osteoclast precursor fusion, while PEST-PTP binding specifically controls TRAP expression, revealing separable anti-osteoclastogenic mechanisms.","evidence":"In vitro osteoclastogenesis with F-BAR, phosphorylation-site, and W232A mutants; in vivo CSF-1R inhibitor rescue in cmo mice","pmids":["22923495"],"confidence":"High","gaps":["Whether PSTPIP2 acts cell-autonomously in osteoclast precursors or via paracrine signaling from macrophages"]},{"year":2014,"claim":"Genetic epistasis with IL-1β, NLRP3, and caspase-1 knockouts identified neutrophil-derived IL-1β processed by serine proteases—not the inflammasome—as the pathogenic driver of cmo disease, redefining the inflammatory mechanism.","evidence":"IL-1RI, IL-1α, IL-1β, NLRP3, and caspase-1 knockout crosses with cmo mice; neutrophil IL-1β secretion with serine protease inhibitors","pmids":["24395802"],"confidence":"High","gaps":["Identity of the specific serine protease(s) processing IL-1β","How PSTPIP2 restrains serine protease activity in neutrophils"]},{"year":2014,"claim":"Discovery that PSTPIP2 modulates LYN/Csk signaling through PEST-PTP recruitment in megakaryocytes extended its signaling-adaptor role beyond macrophages and demonstrated pathway-specific effects on Src family kinases versus ERK.","evidence":"Overexpression and siRNA in K562 cells; W232A mutant; dominant-negative and constitutively active LYN; phospho-signaling analysis","pmids":["24407241"],"confidence":"High","gaps":["Physiological relevance of PSTPIP2 in megakaryopoiesis in vivo","Whether PSTPIP2 directly bridges PEST-PTP to LYN"]},{"year":2015,"claim":"Identification of SHIP1 and Csk as direct PSTPIP2-binding partners, with SHIP1 interacting via C-terminal phosphotyrosines, revealed a PEST-PTP-independent arm of PSTPIP2's anti-inflammatory signaling that restrains IL-1β processing in neutrophils.","evidence":"Co-immunoprecipitation with tyrosine mutant mapping; SHIP1 pharmacological inhibition in primary neutrophils measuring IL-1β","pmids":["26304991"],"confidence":"High","gaps":["Structural basis of the SHIP1–PSTPIP2 interaction","Whether SHIP1 and Csk act redundantly or in the same complex"]},{"year":2018,"claim":"Epigenetic silencing of PSTPIP2 by DNMT3a/DNMT3b-mediated promoter methylation during macrophage activation provided a mechanism for dynamic downregulation of this anti-inflammatory brake, with functional consequences on STAT1-driven M1 polarization.","evidence":"RRBS and ChIP for DNMT3a/3b at Pstpip2 promoter; AAV-PSTPIP2 overexpression in vivo; STAT1/STAT6 signaling in RAW264.7 macrophages","pmids":["29993036","35149186"],"confidence":"Medium","gaps":["Whether DNMT3a-mediated silencing occurs in human macrophages","Direct mechanism by which PSTPIP2 suppresses STAT1 phosphorylation"]},{"year":2022,"claim":"Separation-of-function knock-in mice resolved a long-standing question by showing that the PEST-PTP interaction is the dominant anti-inflammatory axis required to prevent autoinflammatory disease in vivo, while SHIP1 binding provides a secondary layer of IL-1β control.","evidence":"Knock-in mice with mutations disrupting PEST-PTP or SHIP1 binding sites; disease scoring, IL-1β, ROS, and CXCL2 in neutrophils","pmids":["36605205"],"confidence":"High","gaps":["Whether combined disruption of both interactions phenocopies full PSTPIP2 loss","Downstream substrates of PEST-PTPs recruited by PSTPIP2"]},{"year":2024,"claim":"PSTPIP2 was found to regulate NF-κB-dependent IL-19 production in renal tubular epithelial cells and caspase-8-mediated PANoptosis, extending its anti-inflammatory and cytoprotective functions beyond myeloid cells.","evidence":"Conditional Pstpip2 knock-in mice; HDAC inhibitors; caspase-8 activity and PANoptosis markers; IL-19/NF-κB pathway analysis in kidney","pmids":["38314821","38073114"],"confidence":"Medium","gaps":["Whether PSTPIP2 directly engages NF-κB pathway components or acts via its known phosphatase partners in epithelial cells","Independent replication of renal epithelial functions"]},{"year":null,"claim":"Key unresolved questions include: the identity of the serine protease(s) mediating inflammasome-independent IL-1β processing downstream of PSTPIP2 loss, the structural basis for PSTPIP2's multi-partner scaffold function, the specific PEST-PTP substrates that mediate PSTPIP2's dominant anti-inflammatory effect, and whether human PSTPIP2 mutations cause autoinflammatory disease.","evidence":"","pmids":[],"confidence":"High","gaps":["Serine protease identity for IL-1β processing","Structural model of PSTPIP2 F-BAR domain with bound partners","Human genetic disease association"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,6,7,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,7,9,10,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,6,10,12,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,15]}],"complexes":[],"partners":["SHIP1","CSK","PTP-PEST","LYN","PTPN12"],"other_free_text":[]},"mechanistic_narrative":"PSTPIP2 is an F-BAR/PCH domain adaptor protein predominantly expressed in myeloid cells that functions as a negative regulator of innate immune signaling and inflammatory cytokine production while also directly modulating actin cytoskeletal dynamics. PSTPIP2 bundles F-actin to promote filopodia formation and macrophage chemotaxis, and recruits the inhibitory phosphatases PEST-PTPs, SHIP1, and Csk to dampen CSF-1R-dependent ERK signaling, Src family kinase activity, NF-κB, and STAT1 pathways, thereby suppressing osteoclastogenesis, IL-1β processing in neutrophils, reactive oxygen species production, and inflammatory cytokine release [PMID:15788569, PMID:22923495, PMID:26304991, PMID:36605205, PMID:24407241, PMID:29993036]. Separation-of-function knock-in mice demonstrate that PEST-PTP recruitment is the dominant anti-inflammatory interaction, uniquely controlling ROS and chemokine production, while SHIP1 binding contributes to restraining IL-1β output [PMID:36605205]. Loss-of-function mutations in Pstpip2 cause chronic multifocal osteomyelitis in mice through inflammasome-independent, serine protease-dependent excess IL-1β secretion by neutrophils [PMID:16122996, PMID:16397132, PMID:24395802]."},"prefetch_data":{"uniprot":{"accession":"Q9H939","full_name":"Proline-serine-threonine phosphatase-interacting protein 2","aliases":[],"length_aa":334,"mass_kda":38.9,"function":"Binds to F-actin. May be involved in regulation of the actin cytoskeleton (By similarity)","subcellular_location":"Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/Q9H939/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSTPIP2","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/PSTPIP2","total_profiled":1310},"omim":[{"mim_id":"616046","title":"PROLINE/SERINE/THREONINE PHOSPHATASE-INTERACTING PROTEIN 2; PSTPIP2","url":"https://www.omim.org/entry/616046"},{"mim_id":"305371","title":"GATA-BINDING PROTEIN 1; GATA1","url":"https://www.omim.org/entry/305371"},{"mim_id":"259680","title":"CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS 3; CRMO3","url":"https://www.omim.org/entry/259680"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":68.4},{"tissue":"lymphoid tissue","ntpm":60.8},{"tissue":"skeletal muscle","ntpm":30.9}],"url":"https://www.proteinatlas.org/search/PSTPIP2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9H939","domains":[{"cath_id":"1.20.1270.60","chopping":"17-135_211-264","consensus_level":"high","plddt":98.0889,"start":17,"end":264}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H939","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H939-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H939-F1-predicted_aligned_error_v6.png","plddt_mean":89.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSTPIP2","jax_strain_url":"https://www.jax.org/strain/search?query=PSTPIP2"},"sequence":{"accession":"Q9H939","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H939.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H939/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H939"}},"corpus_meta":[{"pmid":"16122996","id":"PMC_16122996","title":"A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis.","date":"2005","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/16122996","citation_count":158,"is_preprint":false},{"pmid":"16397132","id":"PMC_16397132","title":"Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16397132","citation_count":119,"is_preprint":false},{"pmid":"24395802","id":"PMC_24395802","title":"Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24395802","citation_count":96,"is_preprint":false},{"pmid":"20032092","id":"PMC_20032092","title":"Genetic susceptibility factors in a cohort of 38 patients with SAPHO syndrome: a study of PSTPIP2, NOD2, and LPIN2 genes.","date":"2009","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/20032092","citation_count":67,"is_preprint":false},{"pmid":"15788569","id":"PMC_15788569","title":"The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15788569","citation_count":64,"is_preprint":false},{"pmid":"22923495","id":"PMC_22923495","title":"PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22923495","citation_count":62,"is_preprint":false},{"pmid":"19608749","id":"PMC_19608749","title":"Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice.","date":"2009","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/19608749","citation_count":61,"is_preprint":false},{"pmid":"29993036","id":"PMC_29993036","title":"PSTPIP2 connects DNA methylation to macrophage polarization in CCL4-induced mouse model of hepatic fibrosis.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29993036","citation_count":60,"is_preprint":false},{"pmid":"33311489","id":"PMC_33311489","title":"PSTPIP2 inhibits cisplatin-induced acute kidney injury by suppressing apoptosis of renal tubular epithelial cells.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33311489","citation_count":39,"is_preprint":false},{"pmid":"22130530","id":"PMC_22130530","title":"Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), a host membrane-deforming protein, is critical for membranous web formation in hepatitis C virus replication.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22130530","citation_count":29,"is_preprint":false},{"pmid":"26304991","id":"PMC_26304991","title":"PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26304991","citation_count":28,"is_preprint":false},{"pmid":"25602062","id":"PMC_25602062","title":"Increased neutrophil infiltration, IL-1 production and a SAPHO syndrome-like phenotype in PSTPIP2-deficient mice.","date":"2015","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25602062","citation_count":25,"is_preprint":false},{"pmid":"34262554","id":"PMC_34262554","title":"Role of the F-BAR Family Member PSTPIP2 in Autoinflammatory Diseases.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34262554","citation_count":18,"is_preprint":false},{"pmid":"30564127","id":"PMC_30564127","title":"PSTPIP2 Inhibits the Inflammatory Response and Proliferation of Fibroblast-Like Synoviocytes in vitro.","date":"2018","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30564127","citation_count":18,"is_preprint":false},{"pmid":"38073114","id":"PMC_38073114","title":"Histone deacetylase-mediated silencing of PSTPIP2 expression contributes to aristolochic acid nephropathy-induced PANoptosis.","date":"2024","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38073114","citation_count":17,"is_preprint":false},{"pmid":"24407241","id":"PMC_24407241","title":"PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1-deficient megakaryocytes by activating LYN.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24407241","citation_count":16,"is_preprint":false},{"pmid":"35149186","id":"PMC_35149186","title":"DNMT3a-mediated methylation of PSTPIP2 enhances inflammation in alcohol-induced liver injury via regulating STAT1 and NF-κB pathway.","date":"2022","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/35149186","citation_count":14,"is_preprint":false},{"pmid":"31325437","id":"PMC_31325437","title":"PSTPIP2 attenuates joint damage and suppresses inflammation in adjuvant-induced arthritis.","date":"2019","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31325437","citation_count":13,"is_preprint":false},{"pmid":"38314821","id":"PMC_38314821","title":"PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38314821","citation_count":10,"is_preprint":false},{"pmid":"37150118","id":"PMC_37150118","title":"PSTPIP2 alleviates obesity associated adipose tissue inflammation and insulin resistance in diabetes mice through promoting M2 macrophage polarization via activation of PPARγ.","date":"2023","source":"Journal of diabetes and its complications","url":"https://pubmed.ncbi.nlm.nih.gov/37150118","citation_count":9,"is_preprint":false},{"pmid":"36605205","id":"PMC_36605205","title":"Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36605205","citation_count":6,"is_preprint":false},{"pmid":"36324152","id":"PMC_36324152","title":"PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ in the joint microenvironment.","date":"2022","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36324152","citation_count":6,"is_preprint":false},{"pmid":"38824967","id":"PMC_38824967","title":"PSTPIP2 protects against alcoholic liver injury and invokes STAT3-mediated suppression of apoptosis.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38824967","citation_count":3,"is_preprint":false},{"pmid":"37695226","id":"PMC_37695226","title":"PSTPIP2 is associated with disease severity in patients with pressure ulcer sepsis and has anti-inflammatory effects.","date":"2023","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/37695226","citation_count":2,"is_preprint":false},{"pmid":"40503910","id":"PMC_40503910","title":"Disruption of Morrbid alleviates autoinflammatory osteomyelitis in Pstpip2-deficient mice.","date":"2025","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40503910","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.07.687176","title":"Microprotein miP-PSTPIP2 affects cytoskeleton dynamics to modulate endothelial cell endocytosis, barrier function and migration","date":"2025-11-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.07.687176","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.23.634426","title":"Depicting pathogenesis of osteomyelitis by single cell RNA-sequencing and an involvement of <i>Morrbid</i> in the autoinflammatory disease","date":"2025-01-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.23.634426","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16821,"output_tokens":4613,"usd":0.059829},"stage2":{"model":"claude-opus-4-6","input_tokens":8185,"output_tokens":2933,"usd":0.171375},"total_usd":0.231204,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"PSTPIP2 directly bundles F-actin in vitro, and its overexpression in macrophages decreases CSF-1-induced membrane ruffling while increasing filopodia formation, motility, and CSF-1-mediated chemotaxis; PSTPIP2 colocalizes with cortical and filopodial F-actin in vivo.\",\n      \"method\": \"In vitro F-actin bundling assay with purified MAYP/PSTPIP2; overexpression and RNAi knockdown in macrophages with actin phenotype readouts; fluorescence microscopy colocalization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of F-actin bundling plus loss- and gain-of-function cellular assays with defined actin phenotypes\",\n      \"pmids\": [\"15788569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A missense mutation (L98P) in Pstpip2 is the causative genetic lesion for the cmo (chronic multifocal osteomyelitis) mouse autoinflammatory disorder; the L98P mutation results in loss of detectable PSTPIP2 protein in macrophages, mast cells, and osteoclasts.\",\n      \"method\": \"Positional cloning, direct sequencing, backcross mapping to a 1.3 Mb interval on murine chromosome 18\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — positional cloning with direct sequencing replicated across independent labs\",\n      \"pmids\": [\"16122996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A second Pstpip2 missense mutation (I282N, Lupo) causes protein instability and reduces PSTPIP2 expression ~3-fold in macrophages; the autoinflammatory disease is transferable by bone marrow transplantation and develops in the absence of lymphocytes, implicating macrophages as the key effector cell.\",\n      \"method\": \"Positional cloning of ENU-induced mutation; bone marrow transplantation; clodronate liposome macrophage depletion; in vitro cytokine measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — positional cloning plus bone marrow transplant epistasis plus macrophage depletion rescue\",\n      \"pmids\": [\"16397132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PSTPIP2 deficiency causes expansion of macrophage progenitors and increased CSF-1R-dependent ERK1/2 phosphorylation and proliferation in macrophages; retroviral restoration of wild-type PSTPIP2 normalizes aberrant MIP-1α and IL-6 production, placing PSTPIP2 as a negative feedback regulator of CSF-1R signaling.\",\n      \"method\": \"Bone marrow transplantation; retroviral PSTPIP2 rescue; flow cytometry of progenitor populations; intracellular signaling (pERK1/2); cytokine ELISA\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including retroviral rescue and signaling readouts in primary cells\",\n      \"pmids\": [\"19608749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PSTPIP2 suppresses osteoclast development: tyrosine phosphorylation of PSTPIP2 and a functional F-BAR domain are essential for inhibiting TRAP expression and osteoclast precursor fusion, while interaction with PEST-type phosphatases is only required for suppression of TRAP expression. PSTPIP2 deficiency elevates CSF-1R-dependent MIP-1α production, driving osteoclastogenesis.\",\n      \"method\": \"In vitro osteoclastogenesis assay with purified precursors from cmo and Lupo mice; structure-function mutagenesis (F-BAR domain mutants, phosphorylation site mutants, W232A PEST-binding mutant); PLX3397 CSF-1R/c-Kit inhibitor treatment in vivo\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structure-function mutagenesis with defined cellular phenotypes and in vivo pharmacological rescue\",\n      \"pmids\": [\"22923495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-1β (but not IL-1α) drives cmo autoinflammatory disease via an inflammasome-independent, caspase-1-independent pathway; neutrophils (not macrophages) from cmo mice secrete excess IL-1β in response to ATP, silica, and Pseudomonas, and this response is blocked by serine protease inhibitors.\",\n      \"method\": \"Genetic epistasis (IL-1RI-deficient × cmo mice); IL-1α/β cytokine-specific knockout crosses; NLRP3 and caspase-1 knockout crosses; neutrophil-specific IL-1β secretion assay with serine protease inhibitor treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic epistasis crosses with defined pathway placement and pharmacological validation\",\n      \"pmids\": [\"24395802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSTPIP2 is a GATA-1-repressed gene in megakaryocytes; overexpression impairs megakaryocytic differentiation and enhances activation of Src family kinases (specifically LYN) while reducing ERK phosphorylation. The W232A mutation that disrupts PEST phosphatase binding abolishes these effects, indicating that PSTPIP2 acts through PEST phosphatases to modulate CSK/LYN signaling.\",\n      \"method\": \"Ectopic expression and siRNA knockdown in K562 cells; dominant-negative and constitutively active LYN constructs; W232A PEST-binding mutant; phospho-signaling western blots; primary mouse bone marrow megakaryocyte differentiation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with structure-function mutagenesis and multiple orthogonal signaling readouts\",\n      \"pmids\": [\"24407241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSTPIP2 physically interacts with two inhibitory enzymes, SHIP1 and Csk. SHIP1 binds to the critical C-terminal tyrosine residues of PSTPIP2 that are essential for PEST-phosphatase-independent inhibitory function; disruption of this interaction enhances IL-1β processing in neutrophils. PSTPIP2 also binds Csk.\",\n      \"method\": \"Co-immunoprecipitation; mapping of SHIP1 binding to C-terminal PSTPIP2 tyrosines; SHIP1 pharmacological inhibition in neutrophils with IL-1β processing readout\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional validation via pharmacological inhibition in primary neutrophils\",\n      \"pmids\": [\"26304991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PSTPIP2 localizes to detergent-resistant membranes (lipid rafts) containing the HCV RNA replication complex, and its membrane-deforming activity is required for HCV membranous web formation and replication; a PSTPIP2 mutant defective in membrane curvature induction fails to support HCV replication.\",\n      \"method\": \"RNAi knockdown in HCV replicon-harboring and HCV-infected cells; detergent-resistant membrane fractionation; membrane-curvature mutant complementation; HCV protein/RNA quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function plus structure-function mutant with specific mechanistic readout, single lab\",\n      \"pmids\": [\"22130530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mice, disruption of the PEST-PTP binding site in PSTPIP2 causes symptomatic autoinflammatory disease, while disruption of the SHIP1 interaction site does not; both interactions contribute to control of IL-1β production in neutrophils, while PEST-PTPs uniquely regulate reactive oxygen species and CXCL2 chemokine production.\",\n      \"method\": \"Knock-in mouse strains with site-specific mutations disrupting PEST-PTP or SHIP1 binding sites; measurement of disease symptoms, IL-1β, ROS, and CXCL2 in primary neutrophils\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic separation-of-function experiments with multiple orthogonal inflammatory readouts\",\n      \"pmids\": [\"36605205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSTPIP2 hypermethylation by DNMT3a and DNMT3b at the 5'-UTR CpG region silences PSTPIP2 expression in LPS-stimulated macrophages; overexpression of PSTPIP2 inhibits M1 polarization by suppressing STAT1 activity and promotes M2 polarization by enhancing STAT6 activity.\",\n      \"method\": \"Reduced representation bisulfite sequencing (RRBS); ChIP for DNMT3a/3b; AAV9-PSTPIP2 overexpression in vivo; STAT1/STAT6 pathway analysis in RAW264.7 cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP validation of epigenetic mechanism plus pathway-level signaling readouts, single lab\",\n      \"pmids\": [\"29993036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSTPIP2 regulates synovial macrophage polarization and dynamics via estrogen receptor β (ERβ); PSTPIP2-high synovial macrophages form a tight immunological barrier in the joint lining layer, and this polarization effect is dependent on ERβ signaling.\",\n      \"method\": \"Pstpip2-Cre reporter mice; Esr2fl/fl/Adgre-Cre conditional knockout; AAV-mediated PSTPIP2 overexpression; macrophage dynamics and polarization assays in synovial tissue\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic knockouts with reporter mice, single lab\",\n      \"pmids\": [\"36324152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSTPIP2 regulates IL-19 production in damaged renal tubular epithelial cells via suppression of the NF-κB pathway; secreted IL-19 then drives neutrophil extracellular trap (NET) formation via the IL-20Rβ receptor, and NETs in turn promote renal tubular epithelial cell apoptosis.\",\n      \"method\": \"Conditional Pstpip2 knock-in mice; Ly6G neutralizing antibody neutrophil depletion; PAD4 inhibitor NET prevention; in vitro IL-19 neutralization and IL-20Rβ blocking; NF-κB pathway analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic and pharmacological epistasis plus in vitro pathway mapping, single lab\",\n      \"pmids\": [\"38314821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"H3K27ac-mediated histone acetylation at the PSTPIP2 promoter regulates its expression in renal tubular epithelial cells; HDAC inhibition upregulates PSTPIP2 and protects against cisplatin-induced apoptosis. PSTPIP2 overexpression inhibits apoptosis of renal tubular epithelial cells.\",\n      \"method\": \"ChIP assay for H3K27ac at PSTPIP2 promoter; AAV-PSTPIP2 overexpression in vivo; siRNA knockdown in vitro; TSA HDAC inhibitor treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP validation of epigenetic regulation plus in vivo/in vitro functional rescue, single lab\",\n      \"pmids\": [\"33311489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNMT3a directly binds to the Pstpip2 promoter (confirmed by ChIP) and acts as the principal epigenetic repressor of PSTPIP2 expression in alcohol-stimulated macrophages; PSTPIP2 suppresses alcohol-induced inflammation by regulating the STAT1 and NF-κB signaling pathways.\",\n      \"method\": \"ChIP assay for DNMT3a at Pstpip2 promoter; methylation-specific PCR; DNMT3a siRNA knockdown; STAT1 and NF-κB pathway analysis\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirmation of direct promoter binding plus signaling pathway readouts, single lab\",\n      \"pmids\": [\"35149186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSTPIP2 regulates caspase-8 activity in aristolochic acid nephropathy and its loss promotes PANoptosis (pyroptosis, apoptosis, and necroptosis) in renal tubular epithelial cells; HDAC1/HDAC2 suppress PSTPIP2 expression via histone deacetylation.\",\n      \"method\": \"Conditional Pstpip2 knock-in mice; HDAC1/HDAC2 inhibitor (romidepsin); caspase-8 activity measurement; PANoptosis markers in vivo and in vitro\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic model plus pharmacological inhibition with specific caspase-8 mechanistic readout, single lab\",\n      \"pmids\": [\"38073114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSTPIP2 inhibits proliferation and inflammatory response of fibroblast-like synoviocytes via suppression of NF-κB signaling; overexpression reduces NF-κB pathway activity while knockdown promotes it.\",\n      \"method\": \"PSTPIP2 overexpression and siRNA knockdown in AIA rat FLS; NF-κB pathway western blot; proliferation and cytokine assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single cell type, no direct binding demonstration for NF-κB components\",\n      \"pmids\": [\"30564127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSTPIP2 protects against alcoholic liver injury by suppressing hepatocyte apoptosis via the STAT3 signaling pathway; STAT3 was identified as a direct downstream pathway regulated by PSTPIP2 in this context.\",\n      \"method\": \"AAV9-PSTPIP2 overexpression in EtOH-fed mice; stable lentiviral PSTPIP2-overexpressing AML-12 cells; caspase-dependent apoptosis markers; STAT3 pathway analysis\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — gain-of-function with pathway readout but no direct binding or epistasis confirmation for STAT3, single lab\",\n      \"pmids\": [\"38824967\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSTPIP2 is an F-BAR/PCH domain adaptor protein expressed predominantly in myeloid cells that directly bundles F-actin to regulate macrophage filopodia formation and directional motility, and functions as a negative regulator of innate immune signaling by recruiting inhibitory partners PEST-family phosphatases, SHIP1, and Csk to dampen CSF-1R-dependent ERK signaling, Src family kinase (LYN) activity, NF-κB, and STAT1 pathways, thereby suppressing osteoclastogenesis, IL-1β processing by neutrophils, reactive oxygen species production, and inflammatory cytokine release; loss-of-function mutations cause autoinflammatory bone disease in mice through primed myeloid cells and excess IL-1β produced via serine protease-dependent, inflammasome-independent mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSTPIP2 is an F-BAR/PCH domain adaptor protein predominantly expressed in myeloid cells that functions as a negative regulator of innate immune signaling and inflammatory cytokine production while also directly modulating actin cytoskeletal dynamics. PSTPIP2 bundles F-actin to promote filopodia formation and macrophage chemotaxis, and recruits the inhibitory phosphatases PEST-PTPs, SHIP1, and Csk to dampen CSF-1R-dependent ERK signaling, Src family kinase activity, NF-κB, and STAT1 pathways, thereby suppressing osteoclastogenesis, IL-1β processing in neutrophils, reactive oxygen species production, and inflammatory cytokine release [PMID:15788569, PMID:22923495, PMID:26304991, PMID:36605205, PMID:24407241, PMID:29993036]. Separation-of-function knock-in mice demonstrate that PEST-PTP recruitment is the dominant anti-inflammatory interaction, uniquely controlling ROS and chemokine production, while SHIP1 binding contributes to restraining IL-1β output [PMID:36605205]. Loss-of-function mutations in Pstpip2 cause chronic multifocal osteomyelitis in mice through inflammasome-independent, serine protease-dependent excess IL-1β secretion by neutrophils [PMID:16122996, PMID:16397132, PMID:24395802].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing PSTPIP2 as a direct actin regulator resolved how an adaptor protein could reorganize the macrophage cortical cytoskeleton to control motility and membrane dynamics.\",\n      \"evidence\": \"In vitro F-actin bundling with purified PSTPIP2; overexpression/RNAi in macrophages with filopodia and chemotaxis readouts\",\n      \"pmids\": [\"15788569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether actin bundling is separable from the signaling-adaptor function in vivo\", \"Identity of upstream signals regulating PSTPIP2 actin-bundling activity\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Positional cloning of two independent Pstpip2 loss-of-function mutations (L98P in cmo, I282N in Lupo) established that PSTPIP2 is essential for preventing autoinflammatory bone disease, and bone marrow transplant demonstrated a hematopoietic-intrinsic, macrophage-dependent mechanism.\",\n      \"evidence\": \"Positional cloning and sequencing of cmo and Lupo mice; bone marrow transplantation; macrophage depletion rescue\",\n      \"pmids\": [\"16122996\", \"16397132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human PSTPIP2 mutations cause analogous disease\", \"Which downstream inflammatory mediator drives bone pathology\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Retroviral rescue experiments placed PSTPIP2 as a negative feedback regulator of CSF-1R signaling, explaining how its loss causes macrophage progenitor expansion and aberrant cytokine production via excessive ERK1/2 activation.\",\n      \"evidence\": \"Retroviral PSTPIP2 complementation in cmo bone marrow; pERK1/2 and cytokine ELISA in primary macrophages\",\n      \"pmids\": [\"19608749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between PSTPIP2 and CSF-1R signaling components not yet mapped\", \"Contribution of ERK-independent pathways\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Structure-function dissection showed that the F-BAR domain and tyrosine phosphorylation of PSTPIP2 are independently required for suppressing osteoclast precursor fusion, while PEST-PTP binding specifically controls TRAP expression, revealing separable anti-osteoclastogenic mechanisms.\",\n      \"evidence\": \"In vitro osteoclastogenesis with F-BAR, phosphorylation-site, and W232A mutants; in vivo CSF-1R inhibitor rescue in cmo mice\",\n      \"pmids\": [\"22923495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSTPIP2 acts cell-autonomously in osteoclast precursors or via paracrine signaling from macrophages\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis with IL-1β, NLRP3, and caspase-1 knockouts identified neutrophil-derived IL-1β processed by serine proteases—not the inflammasome—as the pathogenic driver of cmo disease, redefining the inflammatory mechanism.\",\n      \"evidence\": \"IL-1RI, IL-1α, IL-1β, NLRP3, and caspase-1 knockout crosses with cmo mice; neutrophil IL-1β secretion with serine protease inhibitors\",\n      \"pmids\": [\"24395802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific serine protease(s) processing IL-1β\", \"How PSTPIP2 restrains serine protease activity in neutrophils\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that PSTPIP2 modulates LYN/Csk signaling through PEST-PTP recruitment in megakaryocytes extended its signaling-adaptor role beyond macrophages and demonstrated pathway-specific effects on Src family kinases versus ERK.\",\n      \"evidence\": \"Overexpression and siRNA in K562 cells; W232A mutant; dominant-negative and constitutively active LYN; phospho-signaling analysis\",\n      \"pmids\": [\"24407241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of PSTPIP2 in megakaryopoiesis in vivo\", \"Whether PSTPIP2 directly bridges PEST-PTP to LYN\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of SHIP1 and Csk as direct PSTPIP2-binding partners, with SHIP1 interacting via C-terminal phosphotyrosines, revealed a PEST-PTP-independent arm of PSTPIP2's anti-inflammatory signaling that restrains IL-1β processing in neutrophils.\",\n      \"evidence\": \"Co-immunoprecipitation with tyrosine mutant mapping; SHIP1 pharmacological inhibition in primary neutrophils measuring IL-1β\",\n      \"pmids\": [\"26304991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SHIP1–PSTPIP2 interaction\", \"Whether SHIP1 and Csk act redundantly or in the same complex\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epigenetic silencing of PSTPIP2 by DNMT3a/DNMT3b-mediated promoter methylation during macrophage activation provided a mechanism for dynamic downregulation of this anti-inflammatory brake, with functional consequences on STAT1-driven M1 polarization.\",\n      \"evidence\": \"RRBS and ChIP for DNMT3a/3b at Pstpip2 promoter; AAV-PSTPIP2 overexpression in vivo; STAT1/STAT6 signaling in RAW264.7 macrophages\",\n      \"pmids\": [\"29993036\", \"35149186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DNMT3a-mediated silencing occurs in human macrophages\", \"Direct mechanism by which PSTPIP2 suppresses STAT1 phosphorylation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Separation-of-function knock-in mice resolved a long-standing question by showing that the PEST-PTP interaction is the dominant anti-inflammatory axis required to prevent autoinflammatory disease in vivo, while SHIP1 binding provides a secondary layer of IL-1β control.\",\n      \"evidence\": \"Knock-in mice with mutations disrupting PEST-PTP or SHIP1 binding sites; disease scoring, IL-1β, ROS, and CXCL2 in neutrophils\",\n      \"pmids\": [\"36605205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether combined disruption of both interactions phenocopies full PSTPIP2 loss\", \"Downstream substrates of PEST-PTPs recruited by PSTPIP2\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"PSTPIP2 was found to regulate NF-κB-dependent IL-19 production in renal tubular epithelial cells and caspase-8-mediated PANoptosis, extending its anti-inflammatory and cytoprotective functions beyond myeloid cells.\",\n      \"evidence\": \"Conditional Pstpip2 knock-in mice; HDAC inhibitors; caspase-8 activity and PANoptosis markers; IL-19/NF-κB pathway analysis in kidney\",\n      \"pmids\": [\"38314821\", \"38073114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PSTPIP2 directly engages NF-κB pathway components or acts via its known phosphatase partners in epithelial cells\", \"Independent replication of renal epithelial functions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the identity of the serine protease(s) mediating inflammasome-independent IL-1β processing downstream of PSTPIP2 loss, the structural basis for PSTPIP2's multi-partner scaffold function, the specific PEST-PTP substrates that mediate PSTPIP2's dominant anti-inflammatory effect, and whether human PSTPIP2 mutations cause autoinflammatory disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Serine protease identity for IL-1β processing\", \"Structural model of PSTPIP2 F-BAR domain with bound partners\", \"Human genetic disease association\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 6, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 7, 9, 10, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 6, 10, 12, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SHIP1\", \"CSK\", \"PTP-PEST\", \"LYN\", \"PTPN12\"],\n    \"other_free_text\": []\n  }\n}\n```"}