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

Abstract

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.

Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition

“…Within the activation of TGF-β signaling pathway, TGF-β1 dimer firstly binds to TGFβR2, outside the cell membrane of the fibroblasts. Next, TGFβR1 is recruited into the complex and phosphorylated by TGFβR2, and then the intracellular signaling pathway is transmitted through canonical pathway (Smad proteins) or non-canonical pathways (MAPKs and Rho family members) 9 , 10 . Indeed, TGF-β1 induced the expression of SRPX2 in a dose and time-depend manner.…”

“…Subsequently, the intracellular signaling pathway of TGF-β receptors is mediated by canonical pathway (Smad proteins) or non-canonical pathways (MAPK and Rho family members) 8 . Both canonical and non-canonical pathways contribute to the differentiation of fibroblasts into alpha-smooth muscle actin (α-SMA) positive myofibroblasts and production of ECM 9 , 10 . Even though suppression of TGF-β is considered theoretically as a feasible approach for the treatment of pulmonary fibrosis, the side effects are unacceptably serious.…”

“…Even though suppression of TGF-β is considered theoretically as a feasible approach for the treatment of pulmonary fibrosis, the side effects are unacceptably serious. As a result, no such agents have been applied in clinical settings so far 9 .…”

The Dynamic Inflammatory Tissue Microenvironment: Signality and Disease Therapy by Biomaterials

“…An endoplasmic reticulum (ER) protein, disulfide isomerase containing thioredoxin domain 5 (TXNDC5), contributes to fibrogenesis by stimulating TGF- β 1 signaling cascade through binding and stabilizing lung TGFBR1. Furthermore, activation of TGF- β 1 upregulates TXNDC5 through an ER stress/ATF6-dependent regulation of lung fibroblasts [ 159 ]. A transcription factor JUN plays a crucial role in the lung fibrogenesis by increasing the expression of CD47, programmed death-ligand 1 (PD-L1), and IL-6.…”

SARS-CoV-2 and Other Respiratory Viruses: What Does Oxidative Stress Have to Do with It?

“…Protein disulfide isomerases (PDIs) constitute a superfamily of redox chaperones that participate in important cellular redox state processes, such as the modulation of cellular oxidative stress mediating homeostasis of the antioxidant glutathione [ 157 ], modulation of endoplasmic reticulum stress, the unfolded protein response, communication between endoplasmic reticulum and mitochondria, and the balance between cell proliferation and apoptosis [ 158 ]. A pulmonary fibrosis study showed that a domain of PDI (TXNDC5) was highly upregulated in patients with idiopathic pulmonary fibrosis as well as a mouse model of this injury, suggesting that this protein could be a novel therapeutic target in the treatment of pulmonary fibrosis [ 159 ]. There are currently no studies showing the effects of PDIs on COVID-19.…”