PSTPIP2

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).

1. 2005 High

   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

   PMID:15788569

   Open questions at the time

   • Whether actin bundling is separable from the signaling-adaptor function in vivo
   • Identity of upstream signals regulating PSTPIP2 actin-bundling activity
2. 2005 High

   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

   PMID:16122996 PMID:16397132

   Open questions at the time

   • Whether human PSTPIP2 mutations cause analogous disease
   • Which downstream inflammatory mediator drives bone pathology
3. 2009 High

   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

   PMID:19608749

   Open questions at the time

   • Direct physical interaction between PSTPIP2 and CSF-1R signaling components not yet mapped
   • Contribution of ERK-independent pathways
4. 2012 High

   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

   PMID:22923495

   Open questions at the time

   • Whether PSTPIP2 acts cell-autonomously in osteoclast precursors or via paracrine signaling from macrophages
5. 2014 High

   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

   PMID:24395802

   Open questions at the time

   • Identity of the specific serine protease(s) processing IL-1β
   • How PSTPIP2 restrains serine protease activity in neutrophils
6. 2014 High

   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

   PMID:24407241

   Open questions at the time

   • Physiological relevance of PSTPIP2 in megakaryopoiesis in vivo
   • Whether PSTPIP2 directly bridges PEST-PTP to LYN
7. 2015 High

   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

   PMID:26304991

   Open questions at the time

   • Structural basis of the SHIP1–PSTPIP2 interaction
   • Whether SHIP1 and Csk act redundantly or in the same complex
8. 2018 Medium

   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

   PMID:29993036 PMID:35149186

   Open questions at the time

   • Whether DNMT3a-mediated silencing occurs in human macrophages
   • Direct mechanism by which PSTPIP2 suppresses STAT1 phosphorylation
9. 2022 High

   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

   PMID:36605205

   Open questions at the time

   • Whether combined disruption of both interactions phenocopies full PSTPIP2 loss
   • Downstream substrates of PEST-PTPs recruited by PSTPIP2
10. 2024 Medium

    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

    PMID:38073114 PMID:38314821

    Open questions at the time

    • Whether PSTPIP2 directly engages NF-κB pathway components or acts via its known phosphatase partners in epithelial cells
    • Independent replication of renal epithelial functions

• 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.
• Serine protease identity for IL-1β processing
• Structural model of PSTPIP2 F-BAR domain with bound partners
• Human genetic disease association