Differential Roles of Cysteinyl Cathepsins in TGF-β Signaling and Tissue Fibrosis

Transforming growth factor beta (TGF-beta) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-beta enhances CatS and CatK expression but reduces CatB and CatL expression in mouse kidney tubular epithelial cells (TECs). CatS- and CatK deficiency reduces TEC nuclear membrane importer importin-beta expression, Smad-2/3 activation, and extracellular matrix (ECM) production. Yet CatB- and CatL-deficiency displays the opposite observations with reduced nuclear membrane exporter RanBP3 expression. CatS and CatK form immunocomplexes with the importin-beta and RanBP3 more effectively than do CatB and CatL. On the plasma membrane, CatS and CatK preferentially form immunocomplexes with and activate TGF-beta receptor-2, whereas CatB and CatL form immunocomplexes with and inactivate TGF-beta receptor-1. Unilateral ureteral obstruction-induced renal injury tests differential cathepsin activities in TGF-beta signaling and tissue fibrosis. CatB- or CatL-deficiency exacerbates fibrosis, whereas CatS- or CatK-deficiency protects kidneys from fibrosis. These cathepsins exert different effects in the TGF-beta signaling cascade independent of their proteolytic properties.