Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
Dr. Yang, Kai-Chien
Nature Communications, Aug 26, 2020
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 TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 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.
特發性肺纖維化 (Idiopathic Pulmonary Fibrosis,IPF) 是一種最常見且最致命的間質性肺病,臨床上可以用於治療IPF患者的藥物選擇很稀少,治療效果也不是很明確,使得IPF病患在治療上遇到許多困難,預後也很差,往往需要進行心肺移植才能存活。因此找出新的IPF致病機轉,並藉此開發新型治療IPF的策略及藥物,對改善IPF患者臨床照護與預後,是一個迫切需要投入研究量能的重要課題。
內質網蛋白TXNDC5是一種蛋白質雙硫異構酶 (protein disulfide isomerase,PDI),主要位於細胞的內質網,其功能被認為和催化蛋白摺疊以及參與胞內氧化還原反應有關。楊老師實驗室團隊於2018年研究發現TXNDC5在心臟纖維化中扮演重要角色(Shih YC and KC Yang, Circ Res 2018, doi: 10.1161/CIRCRESAHA.117.312130)。我們延續在心臟的研究,發現TXNDC5在肺臟纖維化的形成也具有不可或缺的角色。TXNDC5主要透過影響肺臟纖維母細胞中TGFbeta receptor I的穩定性及表現量來強化TGFbeta訊息傳遞路徑,造成肺臟纖維母細胞的大量活化增生及胞外基質堆積,引起肺臟纖維化。研究團隊在IPF病患肺組織以及肺臟纖維母細胞中發現TXNDC5基因及蛋白表達量比正常人高,而在小鼠的肺臟纖維化動物模型中也證實,利用誘導型CRISPR/Cas9基因編輯技術敲除纖維母細胞中TXNDC5基因表現,能有效減緩肺臟纖維化之進程並改善肺功能。未來楊老師團隊也將開發抑制TXNDC5活性的藥物,希望能作為肺臟纖維化病患的新型治療藥物。