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

Abstract

Summary Transforming growth factor beta (TGF-β) signaling contributes to tissue fibrosis. Here we demonstrate that TGF-β 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-β 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-β and RanBP3 more effectively than do CatB and CatL. On the plasma membrane, CatS and CatK preferentially form immunocomplexes with and activate TGF-β receptor-2, whereas CatB and CatL form immunocomplexes with and inactivate TGF-β receptor-1. Unilateral ureteral obstruction-induced renal injury tests differential cathepsin activities in TGF-β 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-β signaling cascade independent of their proteolytic properties.

Cathepsin B Localizes in the Caveolae and Participates in the Proteolytic Cascade in Trabecular Meshwork Cells. Potential New Drug Target for the Treatment of Glaucoma

“…The third factor is TGFβ. As indicated by our results presented here and those in [ 34 ] [ 35 ], there is a complex relationship between CTSB and TGFβ signaling. While decreased levels of TGFβ1 and TGFβ2 were noted in TM cells with knockdown expression of CTSB, the concentration of TGFβ2 in AH from glaucomatous eyes is known to be higher than that in age-matched control eyes.…”

“…Recent reports in the literature have implicated CTSB in TGFβ signaling and epithelial–mesenchymal (EMT) transition [ 19 , 34 , 35 ]. Given the relevance of TGFβ and EMT in glaucoma pathogenesis, we investigated a potential regulatory effect of CTSB in these biological processes in TM cells.…”

“…A role of CTSB in EMT and tissue fibrosis has been investigated in a very recent work [ 34 ]. In this elegant study, Zhang et al report a differential role of cysteine cathepsins in TGFβ signaling and kidney fibrosis.…”

Public Database-Driven Insights Into Aging Stress-Associated Defective Gut Barrier With Low SARS-CoV-2 Receptors

“…Compared to the levels in young age group (aged 20–29 years), expression of ACE2 and TMPRSS2 tended to decrease with age, which was prominent in elderly groups (aged 60–79 years) ( Figure 1A ). For successful viral entry by directly binding to ACE2, other accessary components such as TMPRSS2 and cathepsin L (CTSL) can facilitate S protein priming for receptor binding on the host cell surface ( 10 ); however, CTSL without proteolysis activity on the cell surface is dispensable for host cell entry of SARS-CoV-2 ( 10 , 18 ). In contrast with the levels of ACE2 and TMPRSS2, CTSL expression tended to increase with age in the colon tissue ( Figure 1A ).…”

Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

“…In the murine model of bleomycin-induced pulmonary fibrosis, CatK deficiency associates with severe lesions; CatK inactives proteolytically TGF-β1, thereby supporting that CatK contributes to airway structural integrity [50,51]. Nevertheless, the situation remains highly complex, and diverse data suggest adaptable roles of cathepsins K, S, B and L in TGF-β signaling depending on fibrotic tissues [52]. Cystic fibrosis (CF) is a rare genetic disorder, which leads to an increase in mucus viscosity and its accumulation in the airways, providing a fertile ground for opportunistic pathogens associated with chronic infections and inflammation [53].…”