Characterization of Stat6 protease and Stat5 protease

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Accumulating evidence suggests that STAT-mediated signaling plays critical roles in cell differentiation and/or cell expansion and that thus, STAT-mediated signaling is regulated strictly by many mechanisms. In murine mast cells, when Stat6 is activated by IL-4 and translocated to the nucleus, Stat6 is cleaved by a nucleus-associated protease (namely Stat6-protease). Similarly, the activated Stat5 is cleaved by a protease (Stat5-protease) in the nucleus of myeloid progenitors. These STAT proteases cleave the corresponding STAT proteins at the carboxyl-terminus and the resultant STAT proteins function as dominant negative molecules. Functionally, Stat6-protease protects mast cells from Stat6-dependent growth inhibition while Stat5-protease maintains the immature state of myeloid progenitors. These findings indicate that the proteolytic processing of STAT proteins by the nucleus-associated protease functions as a lineage-specific negative-regulator of STAT-mediated signaling.In the present study, we further characterized these Stat proteases. Interestingly, the activity of Stat6 protease but not of Stat5 protease was inhibited by ONO-5046, a narrow-spectrum elastase inhibitor that inhibits the activity of neutrophil elastase(NE) and proteinase 3(PR3) but not of cathepsin G. Although both NE and PR3 were expressed in bone marrow-derived mast cells and were capable to cleave Stat6 in vitro, our results demonstrated that NE and PR3 differed from mast cell-specific Stat6 protease. These results suggest that Stat6 protease may be an NE-like protease that is exclusively expressed in the nucleus of mast cells.