The Role of Interactions of Adaptor Protein PSTPIP2 in the Development of Autoinflammatory Disease

Abstract

Abstract PSTPIP2 is an adaptor protein, which binds multiple regulators of neutrophil signaling to suppress inflammation. The compete loss of PSTPIP2 protein in the mouse strain Pstpip2cmo results in the development of autoinflammatory disease chronic multifocal osteomyelitis (CMO), a condition resembling human CRMO. The disease is driven by an overproduction of IL-1β and deregulated activity of NADPH oxidase. The main goal of this study is to analyze the effects of PSTPIP2 interactions on leukocyte signaling pathways, IL-1β processing, ROS production by NADPH oxidase, and auto inflammation in vivo. To achieve this, we have generated mice with mutations in major interaction sites in PSTPIP2 including W232 responsible for binding to PEST family phosphatases (PEST-PTP), and the C-terminal sequence containing major tyrosine phosphorylation sites known to bind inositide phosphatase SHIP1 (Pstpip2ΔC-t). W232A mutation resulted in enhanced ROS production by neutrophils and increased IL-1β cleavage. Moreover, some W232A mutants developed CMO symptoms. However, the kinetics was delayed and severity was milder, when compared to Pstpip2cmo strain. In contrast, Pstpip2ΔC-t mutants did not show any CMO symptoms or increased IL-1β cleavage. Interestingly, partially deregulated ROS production could still be measured in Pstpip2ΔC-t neutrophils. Collectively, our data demonstrate an important function of PEST-PTP binding to PSTPIP2 in the suppression of auto inflammation, while SHIP1 binding contributes to the regulation of neutrophil oxidative burst. The obtained data give us a novel perspective on PSTPIP2 interactome and extend our knowledge of the molecular interactions regulating physiological and pathological inflammation.