Endoplasmic reticulum stress-induced apoptosis and autoimmunity in diabetes

Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, 01605-2324, USA.
Current Molecular Medicine (Impact Factor: 3.61). 03/2006; 6(1):71-7. DOI: 10.2174/156652406775574613
Source: PubMed

ABSTRACT Increasing evidence suggests that stress signaling pathways emanating from the endoplasmic reticulum (ER) are important to the pathogenesis of both type 1 and type 2 diabetes. Recent observations indicate that ER stress signaling participates in maintaining the ER homeostasis of pancreatic beta-cells. Either a high level of ER stress or defective ER stress signaling in beta-cells may cause an imbalance in ER homeostasis and lead to beta-cell apoptosis and autoimmune response. In addition, it has been suggested that ER stress attributes to insulin resistance in patients with type 2 diabetes. It is necessary to study the relationship between ER stress and diabetes in order to develop new therapeutic approaches to diabetes based on drugs that block the ER stress-mediated cell-death pathway and insulin resistance.

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    • "The UPR has been implicated in a number of autoimmune disorders associated with vitiligo such as type I diabetes (Lipson et al., 2006). Similar to our proposed model for vitiligo, in diabetes, it has been suggested that exposure to environmental agents such as toxins may be involved in initiation of excessive ER stress in pancreatic β-cells, triggering an apoptotic cascade by the UPR that leads to autoimmunity (Fonseca et al., 2009; Lipson et al., 2006). "
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    ABSTRACT: Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.
    Journal of Investigative Dermatology 06/2012; 132(11):2601-9. DOI:10.1038/jid.2012.181 · 6.37 Impact Factor
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    • "Regulated cell death is a crucial event for development and cell physiology, and alteration of this process could result in the occurrence of severe human diseases such as inflammation, cancer, neoplasia, neurodegeneration or autoimmune disorders [1] [2] [3] [4] [5]. Subcellular organelle stress is observed in many pathological processes, where complex signaling responses mediate the adaptation to stress or trigger apoptosis when a critical threshold of damage is reached [6]. "
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    ABSTRACT: The assembling of distinct signaling protein complexes at the endoplasmic reticulum (ER) membrane controls several stress responses related to calcium homeostasis, autophagy, ER morphogenesis and protein folding. Diverse pathological conditions interfere with the function of the ER altering protein folding, a condition known as "ER stress". Adaptation to ER stress depends on the activation of the unfolded protein response (UPR) and protein degradation pathways such as autophagy. Under chronic or irreversible ER stress, cells undergo apoptosis, where the BCL-2 protein family plays a crucial role at the mitochondria to trigger cytochrome c release and apoptosome assembly. Several BCL2 family members also regulate physiological processes at the ER through dynamic interactomes. Here we provide a comprehensive view of the roles of the BCL-2 family of proteins in mediating the molecular crosstalk between the ER and mitochondria to initiate apoptosis, in addition to their emerging functions in adaptation to stress, including autophagy, UPR, calcium homeostasis and organelle morphogenesis. We envision a model where BCL-2-containing complexes may operate as stress rheostats that, beyond their known apoptosis functions at the mitochondria, determine the amplitude and kinetics of adaptive responses against ER-related injuries. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
    Biochimica et Biophysica Acta 11/2010; 1813(4):564-74. DOI:10.1016/j.bbamcr.2010.11.012 · 4.66 Impact Factor
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    • "For example, gene-expression profiling has demonstrated that the UPR regulates genes involved in protein entry into the ER, folding, glycosylation, ERAD, protein quality control, redox metabolism, autophagy, lipid biogenesis, and vesicular trafficking (Figure 1A). Increasing attention has been given to the regulation of the UPR based on substantial evidence for the involvement of chronic ER stress in many diseases, including neurodegenerative conditions (Matus et al., 2008), cancer (Moenner et al., 2007), diabetes (Lipson et al., 2006), and inflammation (Todd et al., 2008), hence offering new therapeutic targets to treat these diseases. "
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    ABSTRACT: Endoplasmic reticulum (ER) stress is a hallmark feature of secretory cells and many diseases, including cancer, neurodegeneration, and diabetes. Adaptation to protein-folding stress is mediated by the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). The UPR signals through three distinct stress sensors located at the ER membrane-IRE1alpha, ATF6, and PERK. Although PERK and IRE1alpha share functionally similar ER-luminal sensing domains and both are simultaneously activated in cellular paradigms of ER stress in vitro, they are selectively engaged in vivo by the physiological stress of unfolded proteins. The differences in terms of tissue-specific regulation of the UPR may be explained by the formation of distinct regulatory protein complexes. This concept is supported by the recent identification of adaptor and modulator proteins that directly interact with IRE1alpha. In this Review, we discuss recent evidence supporting a model where IRE1alpha signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble.
    Molecular cell 09/2009; 35(5):551-61. DOI:10.1016/j.molcel.2009.08.021 · 14.46 Impact Factor
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