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
收藏
页码：607 / +
页数：25
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