Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands

Ferri, Elena; Thomas, Adrien Le; Wallweber, Heidi Ackerly; Day, Eric S.; Walters, Benjamin T.; Kaufman, Susan; Braun, M.; Clark, Kevin; Beresini, Maureen H.; Mortara, Kyle; Chen, Yung-Chia A.; Canter, Breanna; Phung, Wilson; Liu, Peter S.; Lammens, Alfred; Ashkenazi, Avi; Rudolph, Joachim; Wang, Weiru

doi:10.1038/s41467-020-19974-5

Cited by 27 publications

(30 citation statements)

References 48 publications

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“…Some AIM2 fragments decreased in abundance over time whereas others persisted or even accumulated, suggesting that RIDDLE entails mainly endoribonuclease activity, though exoribonuclease activity against some of the initial products cannot be ruled out. In addition, we treated MDA-MB-231 cells with the previously characterized kinase-directed cellular IRE1α activator, G-9807 62 . This compound induced upregulation of XBP1s, as well as downregulation of the RIDD substrate DGAT2 and the RIDDLE targets TNFAIP8L1 and SIX2 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

Thomas¹,

Ferri²,

Marsters³

et al. 2021

Nat Commun

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Inositol requiring enzyme 1 (IRE1) mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.

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Section: Resultsmentioning

confidence: 99%

Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

Thomas¹,

Ferri²,

Marsters³

et al. 2021

Nat Commun

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“…Moreover, it has been found that G-1749 is structurally similar to the C 31 H 29 ClN 6 O 3 S (KIRA8); however, the two molecules exert opposing effects on the modulation of RNase activity. G-1749 promotes IRE1 RNase activity via occupation of the kinase pocket proximal to the DFG motif, which leads to a distinct conformation of the activation loop (DFG-in or C-helix in), and this mechanism does not stabilize the dimer interface [ 146 ]. These finding suggests that the IRE1 kinase activation loop may play a role in the regulation of RNase activity.…”

Section: Pharmacological Modulation Of Ire1 Activitymentioning

confidence: 99%

The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

et al. 2021

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Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.

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“…IRE1α activation leads to divergent downstream activities including kinase activity, specific Xbp1 splicing activity, and a less specific regulated IRE1-dependent decay (RIDD) activity that degrades ER-associated mRNAs ( Fig. 3 ) ( 66 , 67 ). The RIDD activity of IRE1 has been suggested to degrade INS mRNA itself; interestingly, the protein disulfide isomerase A6 (PDIA6) may counteract this activity ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

“…Reported examples of UPR pathways leading to cell death are mostly limited to downstream mediators in the IRE1 and PERK pathways. IRE1α hyperactivation can lead to cellular demise in other cell types ( 66 ). As discussed above, IRE1α is a bifunctional enzyme with both kinase and endonuclease activities, the latter resulting in specific Xbp1 splicing or nonspecific RIDD degradation of ER-associated RNAs.…”

Section: Introductionmentioning

confidence: 99%

Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells

2021

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Type 2 diabetes (T2D) is a growing cause of poor health, psychosocial burden, and economic costs worldwide. The pancreatic β-cell is a cornerstone of metabolic physiology. Insulin deficiency leads to hyperglycemia, which was fatal before the availability of therapeutic insulins; even partial deficiency of insulin leads to diabetes in the context of insulin resistance. Comprising only an estimated 1 g or <1/500th of a percent of the human body mass, pancreatic β-cells of the islets of Langerhans are a vulnerable link in metabolism. Proinsulin production constitutes a major load on β-cell endoplasmic reticulum (ER), and decompensated ER stress is a cause of β-cell failure and loss in both type 1 diabetes (T1D) and T2D. The unfolded protein response (UPR), the principal ER stress response system, is critical for maintenance of β-cell health. Successful UPR guides expansion of ER protein folding capacity and increased β-cell number through survival pathways and cell replication. However, in some cases the ER stress response can cause collateral β-cell damage and may even contribute to diabetes pathogenesis. Here we review the known beneficial and harmful effects of UPR pathways in pancreatic β-cells. Improved understanding of this stress response tipping point may lead to approaches to maintain β-cell health and function.

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Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands

Cited by 27 publications

References 48 publications

Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α

The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells

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