XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor

Cell. 2001 Dec 28;107(7):881-91. doi: 10.1016/s0092-8674(01)00611-0.

Abstract

In yeast, the transmembrane protein kinase/endoribonuclease Ire1p activated by endoplasmic reticulum stress cleaves HAC1 mRNA, leading to production of the transcription factor Hac1p that activates the unfolded protein response (UPR). In mammals, no Hac1p counterpart has yet been discovered despite the presence of Ire1p homologs in the endoplasmic reticulum. Instead, the transcription factor ATF6 specific to the mammalian UPR is regulated by intramembrane proteolysis. Here, we identified the transcription factor XBP1, a target of ATF6, as a mammalian substrate of such an unconventional mRNA splicing system and showed that only the spliced form of XBP1 can activate the UPR efficiently. Our results reveal features of the UPR conserved during evolution and clarify the relationship between IRE1- and ATF6-dependent pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6
  • Animals
  • Base Sequence
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Protein Folding
  • Protein-Serine-Threonine Kinases*
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism*
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcriptional Activation*

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Atf6 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Fungal Proteins
  • HAC1 protein, S cerevisiae
  • Membrane Glycoproteins
  • RNA, Messenger
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • XBP1 protein, S cerevisiae
  • IRE1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases