Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA

Mol Cell. 2009 Apr 24;34(2):191-200. doi: 10.1016/j.molcel.2009.02.033.


Endoplasmic reticulum (ER) stress triggers the cytoplasmic splicing of XBP1 mRNA by the transmembrane endoribonuclease IRE1alpha, resulting in activation of the unfolded protein response, which maintains ER homeostasis. We show that the unspliced XBP1 (XBP1u) mRNA is localized to the membrane, although its product is neither a secretory nor a membrane protein and is released to the cytosol after splicing. Biochemical and mutagenic analyses demonstrated that membrane localization of XBP1u mRNA required its in-frame translation. An insertional frame-shift mutation greatly diminished both membrane localization and splicing of the XBP1u mRNA. Furthermore, membrane localization was compromised by puromycin treatment and required a hydrophobic region within XBP1u. These data demonstrate that the nascent XBP1u polypeptide recruits its own mRNA to the membrane. This system serves to enhance cytoplasmic splicing and could facilitate a more rapid response to ER stress, and represents a unique way of cotranslational protein targeting coupled to mRNA maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cytoplasm / metabolism*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoribonucleases / metabolism
  • Endoribonucleases / physiology
  • Humans
  • Intracellular Membranes / metabolism*
  • Mice
  • Molecular Sequence Data
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology
  • Protein Structure, Tertiary
  • Protein Transport
  • RNA Splicing*
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism*
  • Regulatory Factor X Transcription Factors
  • Ribosomes / metabolism
  • Transcription Factors / analysis
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • ERN1 protein, human
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases