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Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.
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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WP1665: Limonene and pinene degradation
WP1939: Unfolded Protein Response
WP1675: Nitrogen metabolism
WP1685: Peptidoglycan biosynthesis
WP2199: Seed Development
WP1714: Tyrosine metabolism
WP1527: stress response
WP2292: Chemokine signaling pathway
WP1616: ABC transporters
WP525: Mitochondrial Unfolded-Protein Response
WP2148: Brain derived neurotrophic factor
WP571: FAS pathway and Stress induction of HSP regulation
WP1050: Oxidative Stress
WP1650: Fluorobenzoate degradation
WP1909: Signal regulatory protein (SIRP) family interactions
WP346: Protein Modifications
WP931: G Protein Signaling Pathways
WP1502: Mitochondrial biogenesis
WP1692: Protein export
WP405: Eukaryotic Transcription Initiation
WP948: Eukaryotic Transcription Initiation
WP1531: Vitamin D synthesis
WP1700: Selenoamino acid metabolism
WP2203: TSLP Signaling Pathway
WP707: DNA damage response
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 Divest yourself of a preconceived idea: transcription factor ATF6 is not a soluble protein!
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 ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum.
 Analysis of ATF6 activation in Site-2 protease-deficient Chinese hamster ovary cells.
 Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response.
 ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response.
 Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.
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