Molecular Basis of the Anti-inflammatory Action of MAYP/PSTPIP2

Macrophage actin-associated and tyrosine phosphorylated protein (MAYP), also known as praline- serine- threonine phosphatase-interacting protein 2 (PSTPIP2), belongs to the Pombe Cdc15 homology(PCH) family of proteins that has been shown to coordinate membrane and cytoskeletal dynamics. MAYP is selectively expressed in macrophages, mast cells and osteoclasts and is an actin-bundling protein that regulates filopodia formation and macrophage motililty. PCH proteins play important roles in immunity by regulating the cell surface expression of Fas ligand and cytokine production. Two different mouse MAYP missense mutations, resulting in no (cmo) or low (Lupo) MAYP expression, lead to a psoriatic arthritis-like autoinflammatory disease characterized by ear and paw necrosis, cartilage and bone destruction, indicating that MAYP has an anti-inflammatory activity. The inflammatory diseases in both MAYP mutant mice are mediated by macrophages, which exhibit increased secretion of inflammatory mediators, in particular, Galectin-3 and MIP-1a, without an elevation in their mRNA levels, indicating that MAYP negatively regulates inflammatory mediator release at the post-transcriptional level. MAYP interacts with Galectin-3 and exocytic proteins, providing hypotheses to test concerning its mechanism of action. MAYP mutant macrophages also have decreased phagocytic capacity which may result in their failing to efficiently clear apoptotic bodies, cell debris or pathogens from injured tissue. Our overall hypothesis is that MAYP autoinflammatory disease is due to MAYP deficiency which leads to increased production of inflammatory mediators by macrophages and that disease is further enhanced by macrophage phagocytic defects. The overall aim of this proposal is to establish the molecular basis of MAYP action in regulating macrophage activation. The specific aims are to: 1. Elucidate the mechanism of action of MAYP in regulating Gal-3 and MIP-1a secretion by macrophages. 2. Establish the mechanism by which MAYP deficiency impairs phagocytosis. 3. Determine and utilize the three dimensional structure of MAYP to identify functionally important regions. The proposed experiments will contribute to an understanding of the molecular mechanisms involved in skin inflammation and joint and bone destruction in psoriasis, arthritis and related autoinflammatory disorders. In addition, they will provide a better understanding of the action of PCH proteins in controlling the inflammatory response.