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Published online 6 February 2006. doi:10.1083/jcb.200508145
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 4, 565-575
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Article

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



Hiderou Yoshida1,2, Masaya Oku1, Mie Suzuki1, and Kazutoshi Mori1

1 Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
2 Precursory Research for Embryonic Science and Technology-Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Saitama 332-0012 Japan

Correspondence to Hiderou Yoshida: hide{at}biophysics.mbox.media.kyoto-u.ac.jp

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.

Abbreviations used in this paper: ATF, activating transcription factor; EDEM, ER degradation–enhancing mannosidase-like protein; ERAD, ER-associated protein degradation; ERSE, ER stress response element; HEK, human embryonic kidney; IRE, inositol requiring enzyme; LMB, leptomycin B; NES, nuclear exclusion signal; p, protein; PERK, PKR-like ER-resistant kinase; S, spliced; U, unspliced; XBP1, X-box binding protein 1.


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