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

被引：35

作者：

Zhang, Xian ^{[1
,2
]}

Zhou, Yi ^{[1
,3
]}

Yu, Xueqing ^{[3
]}

Huang, Qin ^{[1
,4
]}

Fang, Wenqian ^{[1
]}

Li, Jie ^{[1
]}

Bonventre, Joseph V. ^{[1
]}

Sukhova, Galina K. ^{[1
]}

Libby, Peter ^{[1
]}

Shil, Guo-Ping ^{[1
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Cardiovasc Med, 77 Ave Louis Pasteur,NRB-7, Boston, MA 02115 USA

[2] Hefei Univ Technol, Sch Food & Biol Engn, Hefei 230009, Anhui, Peoples R China

[3] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Nephrol, Guangzhou 510080, Guangdong, Peoples R China

[4] Southern Med Univ, Nanfang Hosp, Dept Rheumatol, Guangzhou 510515, Guangdong, Peoples R China

来源：

ISCIENCE | 2019年 / 19卷

基金：

美国国家卫生研究院;

关键词：

CELL-CYCLE ARREST; GROWTH-FACTOR-BETA; PROXIMAL TUBULE; RENAL FIBROSIS; KIDNEY-DISEASE; LIVER FIBROSIS; K DEFICIENCY; RECEPTOR; INJURY; MICE;

D O I：

10.1016/j.isci.2019.08.014

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：607 / +

页数：25

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