SnapShot: The Unfolded Protein Response

The Scripps Research Institute, La Jolla, CA, USA
Cell (Impact Factor: 32.24). 02/2010; 140(4):590-590.e2. DOI: 10.1016/j.cell.2010.02.006
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Available from: Rockland Luke Wiseman
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    • "An EVOO secoiridoid-rich extract upregulated the transcriptional expression of the DNAJA4 and DNAJC3 genes, which encodes the ER-localized DNAJ family of proteins[110]. The induced transcription of DNAJ genes is part of the UPR111112113114. The ability of secoiridoids from EVOO to upregulate a set of genes involved in the ER stress response to accumulation of unfolded proteins may appear to conflict with the demonstrated ability of these compounds to strongly inhibit the growth of highly aggressive breast cancer cells[53,115]. "
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    ABSTRACT: Aging is a multifactorial and tissue-specific process involving diverse alterations regarded as the "hallmarks of aging", which include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Virtually all these hallmarks are targeted by dietary olive oil, particularly by virgin olive oil, since many of its beneficial effects can be accounted not only for the monounsaturated nature of its predominant fatty acid (oleic acid), but also for the bioactivity of its minor compounds, which can act on cells though both direct and indirect mechanisms due to their ability to modulate gene expression. Among the minor constituents of virgin olive oil, secoiridoids stand out for their capacity to modulate many pathways that are relevant for the aging process. Attenuation of aging-related alterations by olive oil or its minor compounds has been observed in cellular, animal and human models. How olive oil targets the hallmarks of aging could explain the improvement of health, reduced risk of aging-associated diseases, and increased longevity which have been associated with consumption of a typical Mediterranean diet containing this edible oil as the predominant fat source.
    Full-text · Article · Jan 2016 · Molecules
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    • "Once activated, the three mammalian ER-stress transducers act in a coordinated manner to restore ER homeostasis, not only by increasing the expression of genes encoding chaperones – i.e. the ancestral branch of the UPR – but also by reducing global protein synthesis, which constitutes a rapid adaptive response to stress (Fig. 2). This is mediated by PERK, which, in response to the folding perturbation in the ER or simply when the folding supply does not match the demand, phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α) on residue Ser51 to reduce translation initiation (Wiseman et al., 2010; Cao and Kaufman, 2012). This represents a first line of defense against the threat of protein misfolding. "
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    ABSTRACT: Organisms have evolved mechanisms to cope with and adapt to unexpected challenges and harsh conditions. Unfolded or misfolded proteins represent a threat for cells and organisms, and the deposition of misfolded proteins is a defining feature of many age-related human diseases, including the increasingly prevalent neurodegenerative diseases. These protein misfolding diseases are devastating and currently cannot be cured, but are hopefully not incurable. In fact, the aggregation-prone and potentially harmful proteins at the origins of protein misfolding diseases are expressed throughout life, whereas the diseases are late onset. This reveals that cells and organisms are normally resilient to disease-causing proteins and survive the threat of misfolded proteins up to a point. This Commentary will outline the limits of the cellular resilience to protein misfolding, and discuss the possibility of pushing these limits to help cells and organisms to survive the threat of misfolding proteins and to avoid protein quality control catastrophes.
    Full-text · Article · Oct 2015 · Journal of Cell Science
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    • "In response to disturbed endoplasmic reticulum (ER) homeostasis, signaling pathways known as unfolded protein response (UPR) signaling are induced to restore the protein folding capacity of ER. These signaling pathways are transduced by three sensor proteins PERK, IRE1α, and ATF6α to restore protein folding in a translational-and transcriptional-dependent manner (Wiseman et al., 2010). In addition to this fundamental chaperon function, UPR is found to be associated with the pathogenesis of various diseases/disorders such as inflammation , obesity, diabetes, atherosclerosis and neurodegeneration (Cnop et al., 2012; Wang and Kaufman, 2012; Zhang, 2010; Zhang and Kaufman, 2008). "
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    ABSTRACT: Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses.
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