Abstract |
PSTPIP1 is a cytoskeleton-associated adaptor protein that links PEST-type phosphatases to their substrates. Mutations in PSTPIP1 cause PAPA syndrome ( Pyogenic sterile Arthritis, Pyoderma gangrenosum, and Acne), an autoinflammatory disease. PSTPIP1 binds to pyrin and mutations in pyrin result in familial Mediterranean fever (FMF), a related autoinflammatory disorder. Since disease-associated mutations in PSTPIP1 enhance pyrin binding, PAPA syndrome and FMF are thought to share a common pathoetiology. The studies outlined here describe several new aspects of PSTPIP1 and pyrin biology. We document that PSTPIP1, which has homology to membrane-deforming BAR proteins, forms homodimers and generates membrane-associated filaments in native and transfected cells. An extended FCH (Fes-Cip4 homology) domain in PSTPIP1 is necessary and sufficient for its self-aggregation. We further show that the PSTPIP1 filament network is dependent upon an intact tubulin cytoskeleton and that the distribution of this network can be modulated by pyrin, indicating that this is a dynamic structure. Finally, we demonstrate that pyrin can recruit PSTPIP1 into aggregations (specks) of ASC, another pyrin binding protein. ASC specks are associated with inflammasome activity. PSTPIP1 molecules with PAPA-associated mutations are recruited by pyrin to ASC specks with particularly high efficiency, suggesting a unique mechanism underlying the robust inflammatory phenotype of PAPA syndrome.
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Authors | Andrea L Waite, Philip Schaner, Neil Richards, Banu Balci-Peynircioglu, Seth L Masters, Susannah D Brydges, Michelle Fox, Arthur Hong, Engin Yilmaz, Daniel L Kastner, Ellis L Reinherz, Deborah L Gumucio |
Journal | PloS one
(PLoS One)
Vol. 4
Issue 7
Pg. e6147
(Jul 07 2009)
ISSN: 1932-6203 [Electronic] United States |
PMID | 19584923
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Cytoskeletal Proteins
- MEFV protein, human
- PSTPIP1 protein, human
- Pyrin
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Topics |
- Adaptor Proteins, Signal Transducing
(chemistry, genetics, metabolism)
- Animals
- COS Cells
- Chlorocebus aethiops
- Cytoskeletal Proteins
(chemistry, genetics, metabolism, physiology)
- Fluorescent Antibody Technique
- HeLa Cells
- Humans
- Models, Molecular
- Mutation
- Pyrin
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