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

Taylor W Starnes; David A Bennin; Xinyu Bing; Jens C Eickhoff; Daniel C Grahf; Jason M Bellak; Christine M Seroogy; Polly J Ferguson; Anna Huttenlocher

doi:10.1182/blood-2013-07-516948

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

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

Taylor W Starnes, David A Bennin, Xinyu Bing, Jens C Eickhoff, Daniel C Grahf, Jason M Bellak, Christine M Seroogy, Polly J Ferguson and Anna Huttenlocher

Blood, Vol.123(17), pp.2703-2714

04/24/2014

DOI: 10.1182/blood-2013-07-516948

PMCID: PMC3999755

PMID: 24421327

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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.

Protein Structure, Tertiary

Green Fluorescent Proteins - metabolism

Pyoderma Gangrenosum - metabolism

Arthritis, Infectious - metabolism

Humans

Actins - metabolism

Gene Expression Regulation

Extracellular Matrix - metabolism

Glutathione Transferase - metabolism

DNA - metabolism

Chemotaxis

Inflammation - metabolism

Macrophages - metabolism

Phenotype

Acne Vulgaris - metabolism

Algorithms

Pseudopodia - metabolism

Cytoskeleton - metabolism

Wiskott-Aldrich Syndrome Protein - metabolism

Cytoskeletal Proteins - metabolism

Mutation

Adaptor Proteins, Signal Transducing - metabolism

Microscopy, Fluorescence

RNA, Small Interfering - metabolism

Details

Title: Subtitle: The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages
Creators: Taylor W Starnes - Microbiology Doctoral Training Program
David A Bennin
Xinyu Bing
Jens C Eickhoff
Daniel C Grahf
Jason M Bellak
Christine M Seroogy
Polly J Ferguson
Anna Huttenlocher
Resource Type: Journal article
Publication Details: Blood, Vol.123(17), pp.2703-2714
DOI: 10.1182/blood-2013-07-516948
PMID: 24421327
PMCID: PMC3999755
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Publisher: United States
Grant note: HL-102923 / NHLBI NIH HHS T32 HL007899 / NHLBI NIH HHS UC2 HL102926 / NHLBI NIH HHS P30 CA014520 / NCI NIH HHS T32 AI007635 / NIAID NIH HHS RC2 HL102923 / NHLBI NIH HHS CA085862 / NCI NIH HHS UC2 HL103010 / NHLBI NIH HHS HL007899 / NHLBI NIH HHS R01 CA085862 / NCI NIH HHS HL-102924 / NHLBI NIH HHS UC2 HL102923 / NHLBI NIH HHS RC2 HL102925 / NHLBI NIH HHS RC2 HL103010 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS R01 AR059703 / NIAMS NIH HHS HL114143 / NHLBI NIH HHS HL-103010 / NHLBI NIH HHS RC2 HL102926 / NHLBI NIH HHS T32 GM008692 / NIGMS NIH HHS AR059703 / NIAMS NIH HHS UC2 HL102925 / NHLBI NIH HHS HL-102925 / NHLBI NIH HHS UC2 HL102924 / NHLBI NIH HHS HL-102926 / NHLBI NIH HHS GM008692 / NIGMS NIH HHS F30 HL114143 / NHLBI NIH HHS
Language: English
Date published: 04/24/2014
Academic Unit: Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology
Record Identifier: 9984065840802771

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