ArticleProceedings of the National Academy of Sciences of the United States of America2020
Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 31 citations in OpenAlex.
- SIRT6 Mediates Sterol-Dependent Feedback Regulation of Cholesterol Biosynthetic Genes in Hepatocytes.Biomolecules & therapeutics · 2026Article
- METTL16 Promotes Head and Neck Squamous Cell Carcinoma Progression via m6A-Mediated Stabilization of SREBP2 mRNA and Enhanced Cholesterol Biosynthesis.Cancer medicine · 2026Article
- Cleaved SREBP-2 C-terminal fragment noncanonically drives interleukin-1 receptor-associated kinase 1-dependent apoptosis.Signal transduction and targeted therapy · 2026Article
- Site-1 protease mediated GPC processing is required for persistence of LCMV Clone 13.Npj viruses · 2026Article
- SPRINGing off the lock: the role of SPRING in S1P activity and SREBP-regulated lipid metabolism.Current opinion in lipidology · 2025Review
- SREBP2 as a central player in cancer progression: potential for targeted therapeutics.Frontiers in pharmacology · 2025Review
- Phosphatidic acid directly activates mTOR and then regulates SREBP to promote ganoderic acid biosynthesis under heat stress in Ganoderma lingzhi.Communications biology · 2024Article
- SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain.Nature communications · 2024Article
- Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.Cell reports. Medicine · 2024Article
- Cholesterol metabolism regulator SREBP2 inhibits HBV replication via suppression of HBx nuclear translocation.Frontiers in immunology · 2024Article
- Dysregulated cholesterol regulatory genes in hepatocellular carcinoma.European journal of medical research · 2023Review
- Inhibition of squalene epoxidase linking with PI3K/AKT signaling pathway suppresses endometrial cancer.Cancer science · 2023Article
- Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans.Nature communications · 2023Article
- Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.Cancer discovery · 2023Article
- Endoplasmic Reticulum Stress in Elderly Patients with COVID-19: Potential of Melatonin Treatment.Viruses · 2023Review
- The Non Catalytic Protein ERG28 has a Functional Role in Cholesterol Synthesis and is Coregulated Transcriptionally.Journal of lipid research · 2022Article
- Relationship between protein arginine methyltransferase and cardiovascular disease (Review).Biomedical reports · 2022Review
- Cholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells.Nature communications · 2022Article
- Sulforaphane suppresses the activity of sterol regulatory element-binding proteins (SREBPs) by promoting SREBP precursor degradation.Scientific reports · 2022Article
- Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Lipid homeostasis in animal cells is maintained by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose proteolytic activation requires the cholesterol-sensing membrane protein Scap. In endoplasmic reticulum (ER) membranes, the carboxyl-terminal domain (CTD) of SREBPs binds to the CTD of Scap. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi, where the actions of two proteases release the amino-terminal domains of SREBPs that travel to the nucleus to up-regulate expression of lipogenic genes. The CTD of SREBP remains bound to Scap but must be eliminated so that Scap can be recycled to bind and transport additional SREBPs. Here, we provide insights into how this occurs by performing a detailed molecular dissection of the CTD of SREBP2, one of three SREBP isoforms expressed in mammals. We identify a degradation signal comprised of seven noncontiguous amino acids encoded in exon 19 that mediates SREBP2's proteasomal degradation in the absence of Scap. When bound to the CTD of Scap, this signal is masked and SREBP2 is stabilized. Binding to Scap requires an arginine residue in exon 18 of SREBP2. After SREBP2 is cleaved in Golgi, its CTD remains bound to Scap and returns to the ER with Scap where it is eliminated by proteasomal degradation. The Scap-binding motif, but not the degradation signal, is conserved in SREBP1. SREBP1's stability is determined by a degradation signal in a different region of its CTD. These findings highlight a previously unknown role for the CTD of SREBPs in regulating SREBP activity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.