Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response

Abstract

Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein responseIn the endoplasmic reticulum, unfolded proteins stimulate Ire1 autophosphorylation and RNase activity. The crystal structure of the dephosphorylated kinase/RNase domain of human Ire1 bound to ADP provides insight into the autophosphorylation reaction.

PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism

“…3D). Overexpressed S724A mutant failed to be autophosphorylated at this site located within the structurally disordered central activation segment of IRE1α (12), and blocking its phosphorylation may cause disruption of IRE1α's functional outputs (17,18). Consistently, glucagon increased the phosphorylation at Ser 724 of IRE1α-K599A, which did not alter its inactivity for splicing Xbp1 mRNA (Fig.…”

“…To test if mammalian IRE1α is able to sense changes in metabolic cues, we first examined the phosphorylation status of liver IRE1α in mice under fasted or fed states. In parallel with elevated phosphorylation of cAMP response element-binding protein (CREB), phosphorylation of IRE1α at Ser 724 , a highly conserved positive regulatory site (Ser 841 in yeast Ire1) within its activation segment of the kinase domain (12)(13)(14), markedly increased upon fasting as detected by a phospho-site-specific antibody (Fig. 1A).…”

“…Interestingly, chemical manipulation of the activation mode of IRE1α has been shown to generate alternate RNase outputs (11), suggesting complex structural features of this molecule upon autophosphorylation within its kinase domain to activate its RNase activity. Recently reported crystal structures of the cytoplasmic kinase/endoribonuclease region of yeast Ire1, as well as the dephosphorylated human IRE1α, revealed a dimeric orientation (12,13) or oligomeric arrangements (14) for transautophosphorylation, implying that this kinase is unlikely to be accessible for phosphorylation by other kinases than itself (14) and the XBP1-specific RNase activity is dependent on autophosphorylation (12). However, it remains largely unknown if mechanisms aside from autophosphorylation are operative in activating IRE1, particularly under physiological or pathophysiological conditions.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…All three UPR sensors are maintained in an inactive state through interaction between their ER luminal domains and the protein chaperone immunoglobulin heavy chain-binding protein (BiP; also known as GRP78 and HSP5A). Upon ER stress and loss of ER homeostasis, accumulated unfolded/misfolded proteins in the ER lumen bind and sequester BiP, thereby promoting dissociation of BiP from IRE1α, PERK, and ATF6α (Bertolotti et al 2000;Shen et al 2002;Ali et al 2011). ER stress sensors that are dissociated from BiP induce their downstream TFs through unique mechanisms described below.…”

Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma

“…Sunitinib was shown to reduce XBP1 splicing in multiple myeloma cells, which shows the potential of developing specific kinase inhibitors of IRE1a as a means of modulating the UPR in human cells (71).…”