A recent study identified an inhibitor of IRE1α endoribonuclease activity that did not alter the cellular response to ER stress, but did reduce ER expansion in an exocrine cell model of differentiation. However, the contribution of XBP1 in the IRE1α pathway to placental development has not been addressed. Recently, a role for IRE1α was suggested in the placenta for oxygen/nutrient exchange between the maternal and fetal circulation ( Iwawaki et al., 2009). Mouse genetic studies showed that germline deletion of Xbp1 or Ire1α in mice is embryonic lethal ( Reimold et al., 2000 Zhang et al., 2005). Spliced Xbp1 mRNA is translated into a potent transcription factor, XBP1s, which targets a wide variety of genes encoding proteins involved in ER membrane biogenesis, ER protein folding, ERAD, and protein secretion from the cell ( Lee et al., 2003 Acosta-Alvear et al., 2007). Activated IRE1α cleaves a 26-base fragment from the mRNA encoding the X-box binding protein-1 (XBP1 Yoshida et al., 2001). UPR signaling is mainly mediated through IRE1α, and the function of IRE1β in the UPR is still not clear. IRE1α is expressed in all cells and tissues, whereas IRE1β is specifically expressed in the intestinal epithelium. Mammalian IRE1 has two homologues, IRE1α and IRE1β. IRE1 is the most conserved branch of the UPR, present from yeast to humans. Here, we summarize the adaptive and apoptotic pathways mediated by the UPR and discuss how the UPR responds in different physiological and pathological states. The accessibility to genetically engineered model organisms has further advanced our understanding of the physiological and pathological impacts of the UPR in human physiology and disease. Recent studies on the integration of ER stress signaling pathways with metabolic stress, oxidative stress, and inflammatory response signaling pathways highlight new insights into the diverse cellular processes that are regulated by the UPR ( Hotamisligil, 2010). As a consequence, the UPR regulates the size, the shape ( Schuck et al., 2009), and the components of the ER to accommodate fluctuating demands on protein folding, as well as other ER functions in coordination with different physiological and pathological conditions. The primary signal that activates the UPR is the accumulation of misfolded proteins in the ER lumen ( Dorner et al., 1989). The ER is a highly dynamic organelle and responds to environmental stress and developmental cues through a series of signaling cascades known as the unfolded protein response (UPR Schröder and Kaufman, 2005).
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