Principles of IRE1 modulation using chemical tools.
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.
Program in Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Kenneth P K
KP
Lee
Frank
F
Sicheri
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology; D000071717:X-Box Binding Protein 1
D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases