title: The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages.
abstract: PSTPIP1 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 PSTPIP1 regulates the actin cytoskeleton and contributes to disease pathogenesis remains elusive. Here, we show that endogenous PSTPIP1 negatively regulates macrophage podosome organization and matrix degradation. We identify a novel PSTPIP1-R405C mutation in a patient presenting with aggressive pyoderma gangrenosum. Identification of this mutation reveals that PSTPIP1 regulates the balance of podosomes and filopodia in macrophages. The PSTPIP1-R405C mutation is in the SRC homology 3 (SH3) 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 PSTPIP1-R405C. Our results uncover a novel role for PSTPIP1 and WASP in orchestrating different types of actin-based protrusions. Our findings implicate the cytoskeletal regulatory functions of PSTPIP1 in the pathogenesis of pyoderma gangrenosum and suggest that the cytoskeleton is a rational target for therapeutic intervention in autoinflammatory disease.
authors.affiliation: Microbiology Doctoral Training Program.
authors.forename: Taylor W
authors.initials: TW
authors.lastname: Starnes
authors.forename: David A
authors.initials: DA
authors.lastname: Bennin
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Grahf
authors.forename: Jason M
authors.initials: JM
authors.lastname: Bellak
authors.forename: Christine M
authors.initials: CM
authors.lastname: Seroogy
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: Anna
authors.initials: A
authors.lastname: Huttenlocher
mesh_terms: D000152:Acne Vulgaris / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000465:Algorithms; D001170:Arthritis, Infectious / Q000378:metabolism; D002633:Chemotaxis; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism; D017511:Pyoderma Gangrenosum / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C486382:PSTPIP1 protein, human; D034741:RNA, Small Interfering; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D049452:Green Fluorescent Proteins; D004247:DNA; D005982:Glutathione Transferase