Editorial [Hot Topic: Emerging Roles of the Unfolded Protein Response Signaling in Physiology and Disease (Executive Editor: Claudio A. Hetz and Claudio Soto )]

The viability of a cell strictly depends on the functional and structural integration between different subcellular compartments. At each organelle, different molecular sentinels permanently sense stressful cellular conditions and initiate a complex molecular response. This response aims either to adapt to the new conditions or to activate specific cell death signaling pathways if a critical threshold of damage has been reached. The endoplasmic reticulum (ER) is the subcellular compartment where membrane-spanning and secreted proteins are synthesized. This organelle is responsible for regulating and executing many post-translational modifications, ensuring proper protein folding and facilitating formation of protein complexes. The ER is also the place where the biosynthesis of steroids, cholesterol, and other lipids occurs, playing a crucial role in organelle biogenesis and signaling through the generation of lipid second messengers. The ER is well-known as a major calcium store in the cells and thus constitutes a signaling organelle that modulates many cellular processes including proliferation, cell death and differentiation via calcium release. A number of stress conditions, such as perturbed calcium homeostasis or redox status, elevated rate of secretory protein synthesis, altered glycosylation and cholesterol overloading, can interfere with ER functioning. These alterations lead to the accumulation of unfolded or misfolded proteins in the ER lumen, which has been referred as a cellular condition denominated "ER stress". ER stress triggers a complex adaptive reaction known as the unfolded protein response (UPR), which aims the restoration of the homeostasis of this organelle. Activation of the UPR affects the expression of proteins involved in nearly every aspect of the secretory pathway, including protein entry into the ER, folding, glycosylation, ER-associated degradation (ERAD), ER biogenesis, lipid metabolism and vesicular trafficking. The UPR restores the folding capacity to decrease unfolded protein load. The protective response of the UPR acts transiently to maintain homeostasis within the ER, but sustained ER stress ultimately leads to apoptosis by the activation of specific cell death programs. Increasing evidence indicates that the UPR is crucial for maintaining tissue homeostasis. Different physiological conditions can induce the UPR by increasing the demand of protein synthesis/secretion or by the generation of excessive misfolded proteins as described for B lymphocytes and pancreatic β cells. Also, abnormal metabolic conditions, such as glucose deprivation can trigger the UPR. Components of the ER stress pathway have been shown to be an important factor for tumor survival and growth due to an adaptation to hypoxia conditions. In addition, in different neurodegenerative conditions associated with protein misfolding (including Huntington's disease, Alzheimer's, Prion-related disorders, Amyotrophic Lateral Sclerosis and others), irreversible alteration of ER homeostasis has been proposed to be a critical mediator of neuronal dysfunction. In higher eukaryotes, ER stress stimulates three distinct signaling pathways mediated by the sensors IRE1α (inositol-requiring transmembrane kinase/endonuclease), PERK (double-stranded RNA activated protein kinase-like ER kinase), and ATF6 (activating transcription factor 6) (Fig. 1A). IRE1α is a Ser/Thr protein kinase/endoribonuclease that upon activation initiates the unconventional splicing of the mRNA encoding the transcriptional factor X-Box-binding protein 1 (XBP-1). This leads to the expression of a more stable and potent transcriptional activator, XBP-1s, a basic leucine zipper (bZIP) transcription factor that controls the upregulation of a subset of UPR-related genes. XBP-1 expression also controls organelle biogenesis. In addition, activated IRE1α can bind to the adaptor protein TRAF2 (TNF-associated factor 2), triggering the activation of the c-Jun N-terminal kinase (JNK) pathway (Fig. 1B). PERK directly phosphorylates and inhibits the translation initiation factor eIF2α decreasing the overload of misfolded proteins in this organelle (Fig. 1B). Conversely, eIF2α phosphorylation activates translation of ATF4 (activating transcription factor 4), a transcription factor that induces expression of genes that function in amino acid metabolism, the antioxidant response and apoptosis. A third UPR pathway is initiated by ATF6 (Fig. 1B), a type II ER transmembrane protein encoding a bZIP transcriptional factor on its cytosolic domain and localized in the ER in unstressed cells. Upon ER stress induction, ATF6 is exported to the Golgi, where it is processed. Cleaved ATF6 then translocates to the nucleus where it increases expression of some ER chaperones and XBP-1 transcription. Current models for the.........