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ER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases that Process SREBPs
Open accessAbstract
ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.
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“Accumulation of lipid droplets is a common hallmark of ER stress27,28.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [27]
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Metadata
- Authors
- Ye, J., Rawson, R. B., Komuro, R., Chen, X., Davé, U. P., Prywes, R., Brown, M. S., & Goldstein, J. L.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Columbia University (US)
- Corresponding author
- Brown, Michael S
- Goldstein, Joseph L
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 6
- Issue
- 6
- Pages
- 1355-1364
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2127639686
- Cited by
- 1,871
- References
- 27
- Citations by year
- 2026: 60 · 2025: 58 · 2024: 108 · 2023: 98 · 2022: 87 · 2021: 102 · 2020: 93 · 2019: 89 · 2018: 89 · 2017: 69 · 2016: 83 · 2015: 80 · 2014: 58 · 2013: 96 · 2012: 81
- FWCI
- 16.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- National Cancer Institute (R01CA050329, CA 50329)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- ATF6, endoplasmic reticulum stress, site-1 protease, site-2 protease, proteolytic cleavage, GRP78, SCAP, lipogenesis, unfolded protein response
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, DNA-Binding Proteins, Endoplasmic Reticulum, Heat-Shock Proteins, Humans, Intracellular Membranes, Membrane Proteins, Molecular Sequence Data, Mutation, Endopeptidases, Protein Binding, Protein Processing, Post-Translational, RNA, Messenger, Serine Endopeptidases, Transcription Factors, Transcription, Genetic, Tunicamycin, Immunoblotting, Sequence Alignment, Molecular Chaperones, Thapsigargin, Amino Acid Motifs, CCAAT-Enhancer-Binding Proteins, Proprotein Convertases, Intracellular Signaling Peptides and Proteins, Activating Transcription Factor 6, Sterol Regulatory Element Binding Protein 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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