ArticleMolecular biology of the cell1996
Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.
Article in Molecular biology of the cell, 1996. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 264 papers.
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Who cites it
264 citing papers in PubMed, 595 citations in OpenAlex.
- Triazole Stress Induces Accelerated Degradation ofbioRxiv : the preprint server for biology · 2026Article
- Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts.Nature communications · 2026Review
- Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.Nature communications · 2026Article
- SEL1L3 suppresses colorectal cancer cell growth and metastasis by preventing endoplasmic reticulum-associated degradation of STING.Cell death & disease · 2026Article
- Functional rescue of a disease-linked ERAD pathway mutation via alternative splicing.The EMBO journal · 2026Article
- Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice.The Journal of clinical investigation · 2026Article
- SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The Hrd1-Mediated ERAD Pathway in Plants: Conserved Principles and Plant-Specific Innovations.International journal of molecular sciences · 2026Review
- Functional integrity of the SEL1L-HRD1 complex is critical for endoplasmic reticulum-associated degradation and organismal viability.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Structural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex.Nature communications · 2026Article
- Ubiquitination by HRD1 is essential for TLR3 trafficking and its innate immune signaling.Nature communications · 2025Article
- Competition between Der1 and ERAD-M substrates controls Hrd1 complex function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Engineering the cytochrome P450 to enhance parthenolide production inSynthetic and systems biotechnology · 2025Article
- Hydroxyurea modulates thiol-disulfide homeostasis in the yeast endoplasmic reticulum.Life science alliance · 2025Article
- SEL1L regulates ER homeostasis in Sertoli cells but is dispensable for their function.Molecular biology of the cell · 2025Article
- SEL1L-HRD1-mediated ERAD in mammals.Nature cell biology · 2025Review
- The Erv41-Erv46 complex serves as a retrograde receptor to retrieve misfolded secretory proteins that have escaped from the ER.Molecular biology of the cell · 2025Article
- Coordinated Role of Autophagy and ERAD in Maintaining Neuroendocrine Function by Preventing Prohormone Aggregation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The kinesin Kar3 is required for endoplasmic reticulum-associated degradation.Molecular biology of the cell · 2025Article
- A proteome-wide yeast degron collection for the dynamic study of protein function.The Journal of cell biology · 2025Article
204 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R), a key enzyme of sterol synthesis, is an integral membrane protein of the endoplasmic reticulum (ER). In both humans and yeast, HMG-R is degraded at or in the ER. The degradation of HMG-R is regulated as part of feedback control of the mevalonate pathway. Neither the mechanism of degradation nor the nature of the signals that couple the degradation of HMG-R to the mevalonate pathway is known. We have launched a genetic analysis of the degradation of HMG-R in Saccharomyces cerevisiae using a selection for mutants that are deficient in the degradation of Hmg2p, an HMG-R isozyme. The underlying genes are called HRD (pronounced "herd"), for HMG-CoA reductase degradation. So far we have discovered mutants in three genes: HRD1, HRD2, and HRD3. The sequence of the HRD2 gene is homologous to the p97 activator of the 26S proteasome. This p97 protein, also called TRAP-2, has been proposed to be a component of the mature 26S proteasome. The hrd2-1 mutant had numerous pleiotropic phenotypes expected for cells with a compromised proteasome, and these phenotypes were complemented by the human TRAP-2/p97 coding region. In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound. The Hrd3p protein was homologous to the Caenorhabditis elegans sel-1 protein, a negative regulator of at least two different membrane proteins, and contained an HRD3 motif shared with several other proteins. Hrd1p had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrd1p and Hrd3p proteins conspire to deliver HMG-R to the 26S proteasome. Moreover, our results lend in vivo support to the proposed role of the p97/TRAP-2/Hrd2p protein as a functionally important component of the 26S proteasome. Because the HRD genes were required for the degradation of both regulated and unregulated substrates of ER degradation, the HRD genes are the agents of HMG-R degradation but not the regulators of that degradation.
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