Serine/threonine-protein kinase/endoribonuclease IRE1

Definition:

Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP. Accumulation of misfolded proteins in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity. The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA. The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes. Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A.

References:

[1]. He Piao, et al. Sec16A is critical for both conventional and unconventional secretion of CFTR. Sci Rep. 2017 Jan 9;7:39887. [Content Brief]

[2]. T Iwawaki, et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol. 2001 Feb;3(2):158-64. [Content Brief]

[3]. Heon Yung Gee, et al. Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. Cell. 2011 Sep 2;146(5):746-60. [Content Brief]

[4]. Jiang Liu, et al. A critical role of DDRGK1 in endoplasmic reticulum homoeostasis via regulation of IRE1α stability. Nat Commun. 2017 Jan 27;8:14186. [Content Brief]

[5]. Maruf M U Ali, et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response. EMBO J. 2011 Mar 2;30(5):894-905. [Content Brief]

[6]. Chuan Yin Liu, et al. Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha. J Biol Chem. 2003 May 16;278(20):17680-7. [Content Brief]

[7]. Davide Eletto, et al. Protein disulfide isomerase A6 controls the decay of IRE1α signaling via disulfide-dependent association. Mol Cell. 2014 Feb 20;53(4):562-576. [Content Brief]

[8]. H Yoshida, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001 Dec 28;107(7):881-91. [Content Brief]

[9]. W Tirasophon, et al. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998 Jun 15;12(12):1812-24. [Content Brief]

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