Article

The unfolded protein response: Integrating stress signals through the stress sensor IRE1 α

University of Santiago, Chile, CiudadSantiago, Santiago Metropolitan, Chile
Physiological Reviews (Impact Factor: 29.04). 10/2011; 91(4):1219-43. DOI: 10.1152/physrev.00001.2011
Source: PubMed

ABSTRACT Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

0 Followers
 · 
218 Views
  • Source
    • "The liberated N-terminal cytoplasmic domain is transported into nuclei to activate UPR target genes. Inositol-requiring enzyme 1 is a type I ER-resident transmembrane protein with an ER luminal dimerization and a cytoplasmic domain with Ser/Thr kinase and endonuclease activities (Hetz et al., 2011). ER stress allows IRE1 to autophosphorylate the kinase domain through dimerization and thereby activate the ribonuclease domain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gut-associated lymphoid tissue (GALT) is the biggest lymphoid organ in the body. It plays a role in robust immune responses against invading pathogens while maintaining immune tolerance against nonpathogenic antigens such as foods. Oral vaccination can induce mucosal and systemic antigen-specific immune reactions and has several advantages including ease of administration, no requirement for purification and ease of scale-up of antigen. Thus far, taking advantage of these properties, various plant-based oral vaccines have been developed. Seeds provide a superior production platform over other plant tissues for oral vaccines; they offer a suitable delivery vehicle to GALT due to their high stability at room temperature, ample and stable deposition space, high expression level, and protection from digestive enzymes in gut. A rice seed production system for oral vaccines was established by combining stable deposition in protein bodies or protein storage vacuoles and enhanced endosperm-specific expression. Various types of rice-based oral vaccines for infectious and allergic diseases were generated. Efficacy of these rice-based vaccines was evaluated in animal models. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.
    Plant Biotechnology Journal 06/2015; DOI:10.1111/pbi.12423 · 5.68 Impact Factor
  • Source
    • "This cleaved ATF6 fragment further transcribes chaperones and UPRE to cope with the cellular stress and restore homeostasis (Yoshida et al., 2001; Lee et al., 2002; Harding et al., 2003; Novoa et al., 2003; Wu et al., 2007; Yamamoto et al., 2007; Raven et al., 2008). from the ER to the golgi where it is cleaved by resident proteases like site 1 protease (S1P) and site protease (S2P) (Hetz et al., 2011) to release its cytoplasmic DNA binding fragment called ATF6f. ATF6f increases degradation of unfolded proteins as well as induces the activity of several ER chaperone proteins like BiP, protein disulfide isomerase (PDI) and ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1) (Wu et al., 2007; Yamamoto et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Viruses are excellent vehicles for gene therapy due to their natural ability to infect and deliver the cargo to specific tissues with high efficiency. Although such vectors are usually "gutted" and are replication defective, they are subjected to clearance by the host cells by immune recognition and destruction. Unfolded protein response (UPR) is a naturally evolved cyto-protective signaling pathway which is triggered due to endoplasmic reticulum (ER) stress caused by accumulation of unfolded/misfolded proteins in its lumen. The UPR signaling consists of three signaling pathways, namely PKR-like ER kinase, activating transcription factor 6, and inositol-requiring protein-1. Once activated, UPR triggers the production of ER molecular chaperones and stress response proteins to help reduce the protein load within the ER. This occurs by degradation of the misfolded proteins and ensues in the arrest of protein translation machinery. If the burden of protein load in ER is beyond its processing capacity, UPR can activate pro-apoptotic pathways or autophagy leading to cell death. Viruses are naturally evolved in hijacking the host cellular translation machinery to generate a large amount of proteins. This phenomenon disrupts ER homeostasis and leads to ER stress. Alternatively, in the case of gutted vectors used in gene therapy, the excess load of recombinant vectors administered and encountered by the cell can trigger UPR. Thus, in the context of gene therapy, UPR becomes a major roadblock that can potentially trigger inflammatory responses against the vectors and reduce the efficiency of gene transfer.
    Frontiers in Microbiology 05/2014; 5:250. DOI:10.3389/fmicb.2014.00250 · 3.94 Impact Factor
  • Source
    • "To cope with this stress, cells have developed an adaptive signaling pathway called the unfolded protein response (UPR). The UPR is a complex signal transduction pathway that conveys information about protein folding status in the ER lumen to increase proteinfolding capacity and decrease unfolded protein load [8]. It is characterized by the activation of three distinct signal transduction pathways mediated by inositol requiring (IRE) 1␣, PKR-like ER kinase (PERK), and activating transcription factor (ATF 6␣) [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydroxytyrosol (HT) is a phenolic compound peculiarly abundant in olives and it is being recognized as a protector of LDL from oxidation. In addition to lipid oxidation, one emerging risk factor for cardiovascular disease is ER stress. We tested the effect of HT on the modulation of ER stress in HepG2 cells. HepG2 cells were treated with 1 μM and 5 μM of HT and 100 μM lipoic acid (LA) and glutathione-ethyl ester (GSH), for 24 h. Induction of the unfolded protein response (UPR) was initiated by treatment with 2 μg/mL tunicamycin for 4 h. Real time RT-PCR analyses followed by Western blot and ELISA of different ER stress markers revealed that the protective activities of HT were superior to those of two known thiolic antioxidants, i.e., LA and GSH. Mounting evidence indicates the ER as an important target of dietary or pharmacological intervention. In this paper, we report the modulatory activities of physiological concentrations of HT toward ER stress and we shed some light on pathways alternative to the well-known antioxidant mechanisms, through which olive oil phenolics modulate cell signaling and could impact cardiovascular health and degenerative diseases.
    Molecular Nutrition & Food Research 05/2014; 58(5). DOI:10.1002/mnfr.201300465 · 4.91 Impact Factor
Show more