HtrA1 serine protease inhibits signaling mediated by Tgfβ family proteins

HtrA1, a member of the mammalian HtrA serine protease family, has a highly conserved protease domain followed by a PDZ domain. Because HtrA1 is a secretory protein and has another functional domain with homology to follistatin, we examined whether HtrA1 functions as an antagonist of Tgfβ family proteins. During embryo development, mouse HtrA1 was expressed in specific areas where signaling by Tgfβ family proteins plays important regulatory roles. The GST-pulldown assay showed that HtrA1 binds to a broad range of Tgfβ family proteins, including Bmp4, Gdf5, Tgfβs and activin. HtrA1 inhibited signaling by Bmp4, Bmp2, and Tgfβ1 in C2C12 cells, presumably by preventing receptor activation. Experiments using a series of deletion mutants indicated that the binding activity of HtrA1 required the protease domain and a small linker region preceding it, and that inhibition of Tgfβ signaling is dependent on the proteolytic activity of HtrA1. Misexpression of HtrA1 near the developing chick eye led to suppression of eye development that was indistinguishable from the effects of noggin. Taken together, these data indicate that HtrA1 protease is a novel inhibitor of Tgfβ family members.