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.

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    • "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. "
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    • "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). "
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    • "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]. "
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