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      Endoplasmic reticulum stress in the pathogenesis of fibrotic disease

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      Journal of Clinical Investigation
      American Society for Clinical Investigation

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          Abstract

          <p class="first" id="d722355e129">Eukaryotic cells contain an elegant protein quality control system that is crucial in maintaining cellular homeostasis; however, dysfunction of this system results in endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Severe or prolonged ER stress is associated with the development of degenerative and fibrotic disorders in multiple organs, as evidenced by the identification of disease-causing mutations in epithelial-restricted genes that lead to protein misfolding or mistrafficking in familial fibrotic diseases. Emerging evidence implicates ER stress and UPR signaling in a variety of profibrotic mechanisms in individual cell types. In epithelial cells, ER stress can induce apoptosis, inflammatory signaling, and epithelial-mesenchymal transition. In other cell types, ER stress is linked to myofibroblast activation, macrophage polarization, and T cell differentiation. ER stress–targeted therapies have begun to emerge using approaches that range from global enhancement of chaperone function to selective targeting of activated ER stress sensors and other downstream mediators. As the complex regulatory mechanisms of this system are further clarified, there are opportunities to develop new disease-modifying therapeutic strategies in a wide range of chronic fibrotic diseases. </p>

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          Most cited references106

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          ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

          ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.
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            Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases.

            Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients. Nevertheless, despite its enormous impact on human health, there are currently no approved treatments that directly target the mechanism(s) of fibrosis. The primary goals of this Review series on fibrotic diseases are to discuss some of the major fibroproliferative diseases and to identify the common and unique mechanisms of fibrogenesis that might be exploited in the development of effective antifibrotic therapies.
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              Fibrosis--a common pathway to organ injury and failure.

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                Author and article information

                Journal
                Journal of Clinical Investigation
                American Society for Clinical Investigation
                0021-9738
                1558-8238
                January 2 2018
                January 2 2018
                January 2 2018
                January 2 2018
                January 2 2018
                January 2 2018
                January 2 2018
                January 2 2018
                : 128
                : 1
                : 64-73
                Article
                10.1172/JCI93560
                5749533
                29293089
                606739d2-a084-40f0-88af-819702c41004
                © 2018
                History

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