IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA

• Published in: Nature (London) 2002-01, Vol.415 (6867), p.92-96
• Main Authors: Ron, David, Calfon, Marcella, Zeng, Huiqing, Urano, Fumihiko, Till, Jeffery H, Hubbard, Stevan R, Harding, Heather P, Clark, Scott G
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Caenorhabditis elegans; Caenorhabditis elegans - cytology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Caenorhabditis elegans Proteins - secretion; Cell Line; DNA binding proteins; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - secretion; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - secretion; Fibroblasts; Fundamental and applied biological sciences. Psychology; Genes; Genetic aspects; Humanities and Social Sciences; Introns - genetics; letter; Membrane Proteins; Messenger RNA; Metazoa; Mice; Molecular and cellular biology; Molecular Sequence Data; multidisciplinary; Mutation; Mutation - genetics; Nucleic Acid Conformation; Physiological aspects; Protein Denaturation; Protein Folding; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Regulatory Factor X Transcription Factors; Ribonucleic acid; RNA; RNA Splicing; RNA, Helminth - chemistry; RNA, Helminth - genetics; RNA, Helminth - metabolism; RNA, Messenger - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Stem Cells - metabolism; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - secretion; Worms; X-Box Binding Protein 1; Yeasts
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/415092a

The unfolded protein response (UPR), caused by stress, matches the folding capacity of endoplasmic reticulum (ER) to the load of client proteins in the organelle. In yeast, processing of HAC1 mRNA by activated Ire1 leads to synthesis of the transcription factor Hac1 and activation of the UPR. The responses to activated IRE1 in metazoans are less well understood. Here we demonstrate that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans. Mammalian XBP-1 is essential for immunoglobulin secretion and development of plasma cells, and high levels of XBP-1 messenger RNA are found in specialized secretory cells. Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice. The protein encoded by the processed murine XBP-1 mRNA accumulated during the UPR, whereas the protein encoded by unprocessed mRNA did not. Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity. Our findings suggest that physiological ER load regulates a developmental decision in higher eukaryotes.