Principles of IRE1 modulation using chemical tools

Pak Kin Kenneth Lee, Frank Sicheri

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Citations (Scopus)

Abstract

Perturbations that derail the proper folding and assembly of proteins in the endoplasmic reticulum (ER) lead to misfolded protein accrual in the ER - a toxic condition known as ER stress. The unfolded protein response (UPR) is a signaling system evolved to detect and rectify ER stress. IRE1 is the most ancient member of the ER stress transducers and is conserved in all eukaryotes. In response to ER stress, IRE1 activates a UPR-dedicated transcription factor called X-box binding protein 1 (XBP1) in metazoans (or HAC1 in yeast) to bolster the productive capacity of the ER and purge misfolded proteins from the ER. To activate XBP1/HAC1, IRE1 cleaves XBP1/HAC1 mRNA twice to eliminate an inhibitory intron using a dormant nuclease function in its cytoplasmic effector region (IRE1 cyto ). Recent structural, molecular, and chemical biological approaches have greatly advanced our molecular understanding of how IRE1 transduces ER stress. Here we highlight a sampling of these advances with a bias toward structure and the insights they provide. We also propose a set of principles for IRE1 chemical modulation that may assist in the development of tools to better understand how IRE1 function contributes to health and disease and perhaps ultimately the development of new methods of therapeutic intervention.

Original languageEnglish (US)
Title of host publicationMethods in Enzymology
PublisherAcademic Press Inc.
Pages271-294
Number of pages24
EditionC
DOIs
StatePublished - Jan 1 2011

Publication series

NameMethods in Enzymology
NumberC
Volume490
ISSN (Print)0076-6879

Fingerprint

Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Modulation
Unfolded Protein Response
Carrier Proteins
Proteins
Poisons
Protein Folding
Eukaryota
Transducers
Yeast
Introns
Transcription Factors
Yeasts
Health
Sampling
Messenger RNA
X-Box Binding Protein 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

Cite this

Lee, P. K. K., & Sicheri, F. (2011). Principles of IRE1 modulation using chemical tools. In Methods in Enzymology (C ed., pp. 271-294). (Methods in Enzymology; Vol. 490, No. C). Academic Press Inc.. https://doi.org/10.1016/B978-0-12-385114-7.00016-7
Lee, Pak Kin Kenneth ; Sicheri, Frank. / Principles of IRE1 modulation using chemical tools. Methods in Enzymology. C. ed. Academic Press Inc., 2011. pp. 271-294 (Methods in Enzymology; C).
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Lee, PKK & Sicheri, F 2011, Principles of IRE1 modulation using chemical tools. in Methods in Enzymology. C edn, Methods in Enzymology, no. C, vol. 490, Academic Press Inc., pp. 271-294. https://doi.org/10.1016/B978-0-12-385114-7.00016-7

Principles of IRE1 modulation using chemical tools. / Lee, Pak Kin Kenneth; Sicheri, Frank.

Methods in Enzymology. C. ed. Academic Press Inc., 2011. p. 271-294 (Methods in Enzymology; Vol. 490, No. C).

Research output: Chapter in Book/Report/Conference proceedingChapter

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Lee PKK, Sicheri F. Principles of IRE1 modulation using chemical tools. In Methods in Enzymology. C ed. Academic Press Inc. 2011. p. 271-294. (Methods in Enzymology; C). https://doi.org/10.1016/B978-0-12-385114-7.00016-7