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Vol. 10, Issue 11, 3787-3799, November 1999
HSP Research Institute, Kyoto Research Park, Shimogyo-ku,
Kyoto 600-8813, Japan
The unfolded protein response (UPR) controls the levels of
molecular chaperones and enzymes involved in protein folding in the
endoplasmic reticulum (ER). We recently isolated ATF6 as a candidate for mammalian UPR-specific transcription factor. We report
here that ATF6 constitutively expressed as a 90-kDa protein (p90ATF6)
is directly converted to a 50-kDa protein (p50ATF6) in ER-stressed
cells. Furthermore, we showed that the most important consequence of
this conversion was altered subcellular localization; p90ATF6 is
embedded in the ER, whereas p50ATF6 is a nuclear protein. p90ATF6 is a
type II transmembrane glycoprotein with a hydrophobic stretch in the
middle of the molecule. Thus, the N-terminal half containing a basic
leucine zipper motif is oriented facing the cytoplasm. Full-length ATF6
as well as its C-terminal deletion mutant carrying the transmembrane
domain is localized in the ER when transfected. In contrast, mutant
ATF6 representing the cytoplasmic region translocates into the nucleus
and activates transcription of the endogenous GRP78/BiP gene. We
propose that ER stress-induced proteolysis of membrane-bound p90ATF6
releases soluble p50ATF6, leading to induced transcription in the
nucleus. Unlike yeast UPR, mammalian UPR appears to use a system
similar to that reported for cholesterol homeostasis.
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