![]() Furthermore, the ER lumen has an oxidative environment, which is essential for protein disulphide isomerase (PDI)-mediated disulfide formation (see “Glossary”), a process required for the proper folding of a variety of proteins ( Kim et al., 2008). It is also rich in calcium-dependent molecular chaperones (see “Glossary”) such as ER luminal binding proteins (BiP), calmodulin (CAM), and calreticulin (CRT), which assist in de novo folding or refolding of proteins with high fidelity ( Navazio et al., 2001 Ellgaard and Helenius, 2003 Seo et al., 2008). Indeed, as the major intracellular calcium pool, the ER is the proximal site of a signal transduction cascade that serves to keep cellular homeostasis ( Hendershot, 2004 Kim et al., 2008 Hetz et al., 2011 Hetz, 2012). Therefore, the lumen of the ER needs a unique cellular environment that promotes processing and prevents aggregation ( Anelli and Sitia, 2008 Kim et al., 2008 Hetz et al., 2011 Hetz, 2012). As an organelle for folding and modifications of proteins, the ER is loaded with extremely high concentration of proteins (>100 mg/ml), a concentration at which co-aggregation between proteins and/or polypeptides is clearly promoted ( Stevens and Argon, 1999). Secretory and membrane proteins are synthesized on ribosomes and translocated in an unfolded state into the ER lumen, where they undergo folding, organelle-specific post-translational modifications, and assembly into higher-order structures ( Ellgaard and Helenius, 2003 He and Klionsky, 2009 Marcinak and Ron, 2010). The endoplasmic reticulum (ER) is a membrane-bound compartment that plays important roles in many cellular processes such as calcium homeostasis and protein processing ( Kim et al., 2008 Hetz et al., 2011 Hetz, 2012). This review summarizes current knowledge about the UPR signaling pathways, highlights two identified UPR pathways in plants, and discuss progress in elucidating the UPR in virus-infected cells and its functional roles in viral infection. In virus-infected cells, the cellular translation machinery is hijacked by the infecting virus to produce large amounts of viral proteins, which inevitably perturbs ER homeostasis and causes ER stress. Recently, the essential roles of the UPR have been implicated in a number of mammalian diseases, particularly viral diseases. Activation of these three branch pathways of the UPR leads to the translation arrest and degradation of misfolded proteins, the expression of ER molecular chaperones, and the expansion of the ER membrane to decrease the load of proteins and increase the protein-folding capacity in the ER. The UPR signaling network encompasses three core elements, i.e., PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein-1 (IRE1). The accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) results in ER stress that triggers cytoprotective signaling pathways, termed the unfolded protein response (UPR), to restore and maintain homeostasis in the ER or to induce apoptosis if ER stress remains unmitigated. Southern Crop Protection and Food Research Centre, Agriculture and Agri-Food Canada, London, ON, Canada.
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