The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages.

[wiskott-aldrich syndrome]

PSTPIP 1 is a cytoskeletal adaptor and F-BAR protein that has been implicated in autoinflammatory disease , most notably in the PAPA syndrome : pyogenic sterile arthritis , pyoderma gangrenosum , and acne . However , the mechanism by which PSTPIP 1 regulates the actin cytoskeleton and contributes to disease pathogenesis remains elusive . Here , we show that endogenous PSTPIP 1 negatively regulates macrophage podosome organization and matrix degradation . We identify a novel PSTPIP 1 -R 405 C mutation in a patient presenting with aggressive pyoderma gangrenosum . Identification of this mutation reveals that PSTPIP 1 regulates the balance of podosomes and filopodia in macrophages . The PSTPIP 1 -R 405 C mutation is in the SRC homology 3 (SH 3 ) domain and impairs Wiskott-Aldrich syndrome protein (WASP ) binding , but it does not affect interaction with protein-tyrosine phosphatase (PTP )-PEST . Accordingly , WASP inhibition reverses the elevated F-actin content , filopodia formation , and matrix degradation induced by PSTPIP 1 -R 405 C . Our results uncover a novel role for PSTPIP 1 and WASP in orchestrating different types of actin-based protrusions . Our findings implicate the cytoskeletal regulatory functions of PSTPIP 1 in the pathogenesis of pyoderma gangrenosum and suggest that the cytoskeleton is a rational target for therapeutic intervention in autoinflammatory disease .

Diseases
Validation

Diseases presenting "arthritis" symptom

acute rheumatic fever

child syndrome

congenital adrenal hyperplasia

cystinuria

familial hypocalciuric hypercalcemia

familial mediterranean fever

focal myositis

harlequin ichthyosis

homocystinuria without methylmalonic aciduria

inclusion body myositis

lamellar ichthyosis

malignant atrophic papulosis

pyomyositis

sneddon syndrome

trochlear dysplasia

typhoid

wiskott-aldrich syndrome

This symptom has already been validated