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

Xian Zhang; Yi Zhou; Xueqing Yu; Qin Huang; Wenqian Fang; Jie Li; Joseph V Bonventre; Galina K Sukhova; Peter Libby; Guo-Ping Shi

doi:10.1016/j.isci.2019.08.014

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

iScience. 2019 Sep 27:19:607-622. doi: 10.1016/j.isci.2019.08.014. Epub 2019 Aug 9.

Authors

Xian Zhang¹, Yi Zhou², Xueqing Yu³, Qin Huang⁴, Wenqian Fang⁵, Jie Li⁵, Joseph V Bonventre⁵, Galina K Sukhova⁵, Peter Libby⁵, Guo-Ping Shi⁶

Affiliations

¹ Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA; School of Food & Biological Engineering, Hefei University of Technology, Hefei 230009, China.
² Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA; Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
³ Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
⁴ Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA; Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
⁵ Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA.
⁶ Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115, USA. Electronic address: gshi@bwh.harvard.edu.

Abstract

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.

Keywords: Fibrosis; Functional Aspects of Cell Biology; Molecular Mechanism of Behavior.

Abstract

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