PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk

摘要: Mutations in the adaptor protein PSTPIP2 are cause of autoinflammatory disease chronic multifocal osteomyelitis mice. This closely resembles human disorder recurrent osteomyelitis, characterized by sterile inflammation bones and often associated with other organs, such as skin. The most critical process disease’s development is enhanced production IL-1β. excessive IL-1β likely produced neutrophils. In addition, increased activity macrophages, osteoclasts, megakaryocytes has also been described. However, molecular mechanism how deficiency results this phenotype poorly understood. Part inhibitory function mediated tyrosine phosphatases from proline-, glutamic acid-, serine- threonine-rich (PEST) family, which known to interact central part protein, but regions not required for PEST-family phosphatase binding were shown be indispensable function. article, we show that binds enzymes Csk SHIP1. interaction SHIP1 particular importance because it residues at C terminus PSTPIP2, crucial its PEST-phosphatase–independent effects different cellular systems. We demonstrate neutrophils region important PSTPIP2-mediated suppression processing inhibition enhancement processing. describe deregulated neutrophil response multiple activators, including silica, Ab aggregates, LPS, suggestive a rather generalized hypersensitivity these cells various external stimulants.