ArticleProceedings of the National Academy of Sciences of the United States of America2016
Direct and essential function for Hrd3 in ER-associated degradation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 71 citations in OpenAlex.
- Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts.Nature communications · 2026Review
- SEL1L3 suppresses colorectal cancer cell growth and metastasis by preventing endoplasmic reticulum-associated degradation of STING.Cell death & disease · 2026Article
- 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
- Limiting ER-associated degradation capacity triggers acute and chronic effects on insulin biosynthesis.The Journal of clinical investigation · 2026Article
- 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
- Lipid bilayer thinning near a ubiquitin ligase selects ER membrane proteins for degradation.bioRxiv : the preprint server for biology · 2025Article
- ERAD machinery controls the conditional turnover of PIN-LIKES in plants.Science advances · 2025Article
- SEL1L-HRD1-mediated ERAD in mammals.Nature cell biology · 2025Review
- The transcription factor CfHac1 regulates the degradation of ubiquitin-mediated ER-associated misfolded proteins and pathogenicity in Colletotrichum fructicola.Stress biology · 2025Article
- Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons.Nature communications · 2024Article
- SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.Nature communications · 2024Article
- Direct observation of autoubiquitination for an integral membrane ubiquitin ligase in ERAD.Nature communications · 2024Article
- Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis.Nature communications · 2024Article
- Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders.The Journal of clinical investigation · 2024Article
- Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death.The Journal of clinical investigation · 2024Article
- SEL1L-HRD1 ER-associated degradation regulates leptin receptor maturation and signaling in POMC neurons in diet-induced obesity.Research square · 2024Article
- The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes.Nature communications · 2023Article
- The Role of the Rhomboid Superfamily in ER Protein Quality Control: From Mechanisms and Functions to Diseases.Cold Spring Harbor perspectives in biology · 2023Review
- SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer.iScience · 2022Article
- A positive genetic selection for transmembrane domain mutations in HRD1 underscores the importance of Hrd1 complex integrity during ERAD.Current genetics · 2022Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The HRD (HMG-CoA reductase degradation) pathway is a conserved route of endoplasmic reticulum-associated degradation (ERAD), by which misfolded ER proteins are ubiquitinated and degraded. ERAD substrates are ubiquitinated by the action of the Hrd1 RING-H2 E3 ligase. Hrd1 is always present in a stoichiometric complex with the ER membrane protein Hrd3, which is also required for HRD-dependent degradation. Despite its conserved presence, unequivocal study of Hrd3 function has been precluded by its central role in Hrd1 stability. Loss of Hrd3 causes unrestricted self-degradation of Hrd1, resulting in significant loss of the core ligase. Accordingly, the degree to which Hrd3 functions independently of Hrd1 stabilization has remained unresolved. By capitalizing on our studies of Usa1 in Hrd1 degradation, we have devised a new approach to evaluate Hrd3 functions in ERAD. We now show that Hrd3 has a direct and critical role in ERAD in addition to Hrd1 stabilization. This direct component of Hrd3 is phenotypically as important as Hrd1 in the native HRD complex. Hrd3 was required the E3 activity of Hrd1, rather than substrate or E2 recruitment to Hrd1. Although Hrd1 can function in some circumstances independent of Hrd3, these studies show an indispensable role for Hrd3 in living cells.
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