pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response

J Cell Biol. 2006 Feb 13;172(4):565-75. doi: 10.1083/jcb.200508145. Epub 2006 Feb 6.


Upon the accumulation of unfolded proteins in the mammalian endoplasmic reticulum (ER), X-box binding protein 1 (XBP1) premessenger RNA (premRNA) is converted to mature mRNA by unconventional splicing that is mediated by the endonuclease inositol-requiring enzyme 1. The transcription factor protein (p) XBP1 spliced (S), which is translated from mature XBP1 mRNA, contains the nuclear localization signal and the transcriptional activation domain and activates the transcription of target genes, including those encoding ER chaperones in the nucleus. We show that pXBP1 unspliced (U) encoded in XBP1 pre-mRNA was constitutively expressed and markedly accumulated at the recovery phase of ER stress. pXBP1(U) contained the nuclear exclusion signal instead of the transcriptional activation domain and shuttled between the nucleus and the cytoplasm. Interestingly, pXBP1(U) formed a complex with pXBP1(S), and the pXBP1(U)-pXBP1(S) complex was sequestered from the nucleus. Moreover, the complex was rapidly degraded by proteasomes because of the degradation motif contained in pXBP1(U). Thus, pXBP1(U) is a negative feedback regulator of pXBP1(S), which shuts off the transcription of target genes during the recovery phase of ER stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Dithiothreitol / pharmacology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Feedback, Physiological / drug effects
  • Gene Expression Regulation / drug effects
  • HeLa Cells
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Protein Folding*
  • Protein Splicing / physiology*
  • Protein Transport / drug effects
  • RNA Precursors / genetics
  • RNA Precursors / metabolism*
  • RNA, Messenger / biosynthesis
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA Precursors
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Cycloheximide
  • Dithiothreitol