Key Points• PSTPIP1 regulates the transition from podosomes to filopodia in macrophages by modulating WASP activity.• The novel PSTPIP1-R405C mutant induces filopodia formation, increases matrix degradation, and is associated with severe pyoderma gangrenosum.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. (Blood. 2014;123(17):2703-2714 Introduction Dynamic regulation of the actin cytoskeleton and cell migration is essential for cellular immunity, because leukocytes travel long distances between tissues to perform their effector functions. Indeed, immunodeficiency syndromes, including Wiskott-Aldrich syndrome, leukocyte adhesion deficiency, and warts-hypogammaglobulinemiainfections-myelokathexis syndrome, are secondary to defects in the cytoskeleton and motility of leukocytes.1 Colchicine, which inhibits microtubule polymerization, is used to treat inflammatory conditions, and several other compounds that target cell motility are in development as immunomodulators, which indicates the importance of regulating the cytoskeleton to control immunity and inflammation.2,3 Conversely, neutrophils from patients with the autoinflammatory disease, neonatal onset multisystem inflammatory disease/ Muckle-Wells syndrome, have impaired chemotaxis, which suggests that altered leukocyte migration may also promote a proinflammatory state. 4 While altered leukocyte motility has been established as a cause of immunodeficiency, the role of cytoskeletal dysregulation and altered motility in inflammation and tissue damage remains poorly characterized.Proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) is a cytoskeleton-associated adaptor and F-BAR domaincontaining protein that is linked to PAPA syndrome, the human inflammatory disea...

Cystic echinococcosis (CE) is an infection caused by the Echinococcus granulosus tapeworm. CE generally manifests in the liver, but it may present in any organ. These patients often first present to the emergency department. Mortality over 10 years is significant for those who go undiagnosed. We report the case of a 34-year-old patient who immigrated from Yemen six years earlier. She presented with acute onset dysuria, suprapubic pain, and fever. Imaging revealed a primary multicystic mass on the right renal pole with a secondary lesion in the right hepatic lobe. On further investigation, the patient’s serum was positive for echinococcus antibodies.

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