Abstract
The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. The resolution of the UPR is directed by PPP1R15A (GADD34) and leads to the restoration of normal ribosomal activity. While the role of PPP1R15A has been explored in lung epithelial cells, the role of this UPR resolving factor has yet to be explored in lung mesenchymal cells. The objective of the current study was to determine the expression and role of PPP1R15A in IPF fibroblasts and in a bleomycin-induced lung fibrosis model. A survey of IPF lung tissue revealed that PPP1R15A expression was markedly reduced. Targeting PPP1R15A in primary fibroblasts modulated TGF-β-induced fibroblast to myofibroblast differentiation and exacerbated pulmonary fibrosis in bleomycin-challenged mice. Interestingly, the loss of PPP1R15A appeared to promote lung fibroblast senescence. Taken together, our findings demonstrate the major role of PPP1R15A in the regulation of lung mesenchymal cells, and regulation of PPP1R15A may represent a novel therapeutic strategy in IPF.
Highlights
The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in Idiopathic pulmonary fibrosis (IPF)
Many genes were up-regulated, including the unfolded protein sensor BiP (HSPA5), PERK (EIF2AK3, the mediator of the translation arm of the UPR) along with many of the components of the endoplasmic-reticulum-associated protein degradation (ERAD) complex that lies downstream of both the IRE1/ERN1 and ATF6 UPR pathways. Of those genes down-regulated in IPF, the majority were those transcriptionally regulated by ATF4 and include PPP1R15A, DDIT3, and ATF4 itself
We show that the UPR/ER stress pathway is altered in two large transcriptomics studies employing IPF lung samples[22,23] and in both studies the PERK/EIF2AK3 pathway and the IRE1 pathway were activated in IPF compared with normal lung (Fig. 1)
Summary
The unfolded protein response (UPR) is a direct consequence of cellular endoplasmic reticulum (ER) stress and a key disease driving mechanism in IPF. Normal alveolar lung tissue is replaced by excess extracellular matrix as a consequence of aberrant mesenchymal cell proliferation and activation[2]. These mechanisms are often linked to an impaired wound healing r esponse[3]. Cellular senescence of several cell types including epithelial cells and fibroblasts in the lungs of IPF patients appears to contribute to protein-misfolding stress and to stimulation of the UPR15. Growing evidence suggests that the targeting of senescent cells via senolytic strategies might provide therapeutic benefit in IPF possibly due to the attenuation of U PR17
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