Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization

被引：100

作者：

Lee, Tzu-Han ^{[1
]}

Yeh, Chih-Fan ^{[1
,2
,3
]}

Lee, Ying-Tung ^{[1
]}

Shih, Ying-Chun ^{[1
]}

Chen, Yen-Ting ^{[1
]}

Hung, Chen-Ting ^{[1
]}

You, Ming-Yi ^{[1
]}

Wu, Pei-Chen ^{[1
]}

Shentu, Tzu-Pin ^{[4
]}

Huang, Ru-Ting ^{[4
]}

Lin, Yu-Shan ^{[1
]}

Wu, Yueh-Feng ^{[5
,6
]}

Lin, Sung-Jan ^{[5
,6
,7
,8
,9
]}

Lu, Frank-Leigh ^{[10
]}

Tsao, Po-Nien ^{[9
,10
]}

Lin, Tzu-Hung ^{[11
]}

Lo, Shen-Chuan ^{[11
]}

Tseng, Yi-Shuan ^{[1
]}

Wu, Wan-Lin ^{[1
]}

Chen, Chiung-Nien ^{[12
]}

Wu, Chau-Chung ^{[2
,3
,13
]}

Lin, Shuei-Liong ^{[9
,14
,15
]}

Sperling, Anne, I ^{[4
]}

Guzy, Robert D. ^{[4
]}

Fang, Yun ^{[4
]}

Yang, Kai-Chien ^{[1
,2
,3
,9
,16
]}

机构：

[1] Natl Taiwan Univ, Coll Med, Dept & Grad Inst Pharmacol, Taipei, Taiwan

[2] Natl Taiwan Univ Hosp, Dept Internal Med, Div Cardiol, Taipei, Taiwan

[3] Natl Taiwan Univ Hosp, Cardiovasc Ctr, Taipei, Taiwan

[4] Univ Chicago, Dept Med, Sect Pulm & Crit Care, 5841 S Maryland Ave, Chicago, IL 60637 USA

[5] Natl Taiwan Univ, Coll Med, Dept Biomed Engn, Taipei, Taiwan

[6] Natl Taiwan Univ, Coll Engn, Taipei, Taiwan

[7] Natl Taiwan Univ Hosp, Dept Dermatol, Taipei, Taiwan

[8] Coll Med, Taipei, Taiwan

[9] Natl Taiwan Univ, Res Ctr Dev Biol & Regenerat Med, Taipei, Taiwan

[10] Natl Taiwan Univ Hosp, Dept Pediat, Taipei, Taiwan

[11] Ind Technol Res Inst, Mat & Chem Res Labs, Zhudong, Taiwan

[12] Natl Taiwan Univ Hosp, Dept Surg, Taipei, Taiwan

[13] Natl Taiwan Univ, Coll Med, Dept & Grad Inst Med Educ & Bioeth, Taipei, Taiwan

[14] Natl Taiwan Univ, Coll Med, Dept & Grad Inst Physiol, Taipei, Taiwan

[15] Natl Taiwan Univ Hosp, Dept Internal Med, Div Nephrol, Taipei, Taiwan

[16] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

MESENCHYMAL TRANSITION; INHIBITION; INDUCTION; PATHWAYS; FAMILY; TRIAL;

D O I：

10.1038/s41467-020-18047-x

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：

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGF beta 1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGF beta 1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.

引用

页数：20

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