Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts.

Abstract:

:Accumulation of misfolded proteins within the lumen of the mammalian endoplasmic reticulum (ER) activates the unfolded protein response (UPR). ATF6 and Ire1p are ER-associated proteins that control UPR-specific transcription systems in mammals; UPR signaling involves cleavage of ATF6 and splicing of XBP1 mRNA initiated by Ire1p. We tested the hypothesis that activation of ATF6 and/or Ire1p determines the levels of mRNAs derived from target genes encoding GRP78/BiP and EDEM. By subjecting dermal fibroblasts to multiple stresses, strong correlations were found between ATF6 activation and XBP1 splicing, and between GRP78/BiP mRNA and EDEM mRNA accumulation. Surprisingly, there was no reasonable correlation between activation of either signal transducer with accumulation of either target transcript. Thus, ATF6 and Ire1p signaling do not define the magnitude of UPR-dependent mRNA increases, even though they may be necessary for gene activation, suggesting the existence of additional stress-sensitive factors acting as "coincidence detectors" for transcript accumulation.

authors

Shang J,Lehrman MA

doi

10.1016/j.bbrc.2004.03.058

subject

Has Abstract

pub_date

2004-04-30 00:00:00

pages

390-6

issue

2

eissn

0006-291X

issn

1090-2104

pii

S0006291X04005467

journal_volume

317

pub_type

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