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Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis
Abstract
Significance: Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control production of cholesterol and other lipids. In endoplasmic reticulum (ER) membranes, SREBPs form complexes with Scap, a cholesterol-sensing membrane protein. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi where proteolytic cleavage releases the transcription factor domain that turns on genes involved in cholesterol synthesis. The remainder of SREBP still bound to Scap must be eliminated so that Scap can be recycled to bind additional SREBPs. Here, we discover a degradation signal in SREBP that mediates clearance of the cleaved SREBP fragments from Scap. Such clearance is essential for the recycling of Scap and thus it is a central step in regulation of cholesterol homeostasis.
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“At the same time, SCAP and the remnant C-terminal domain of SREBP undergo retrograde transport to the ER, where remnant SREBP is degraded and SCAP can enter a new cycle of SREBP activation1,9.”
From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [9]
Citations
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Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation
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Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans
Hendrix, S., Kingma, J., Ottenhoff, R., Valiloo, M., Svecla, M., Zijlstra, L. F., Sachdev, V., Kovac, K., Levels, J. H. M., Jongejan, A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40943-1 · Cited by 34
Zhang, F., Gao, J., Liu, X., Sun, Y., Liu, L., Hu, B., Wang, Z., Shi, J., Guo, W., & Zhang, S. (2023) · Molecular Carcinogenesis · doi:10.1002/mc.23538 · Cited by 12
Metadata
- Authors
- Kober, D. L., Xu, S., Li, S., Bajaj, B., Liang, G., Rosenbaum, D. M., & Radhakrishnan, A.
- Affiliations
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-10-26
- Volume
- 117
- Issue
- 45
- Pages
- 28080-28091
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 33
- References
- 2
- Language
- en
- Funders
- HHS | National Institutes of Health (HL20948, GM116387)
- Welch Foundation (I-1793, I-1770)
- Fondation Leducq (19CVD04)
- American Heart Association (18POST34080141)
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- The paper
- Kober, D. L., Xu, S., Li, S., Bajaj, B., Liang, G., Rosenbaum, D. M., & Radhakrishnan, A. (2020). Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2018578117
