ArticleMolecular biology of the cell2018
The degradation pathway of a model misfolded protein is determined by aggregation propensity.
Article in Molecular biology of the cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Ubiquitin chain variability directs substrates of the Tul1 ubiquitin ligase complex to different degradation pathways.The Journal of cell biology · 2025Article
- Cell-Based Small-Molecule Screening Identifying Proteostasis Regulators Enhancing Factor VIII Missense Mutant Secretion.Biomolecules · 2025Article
- Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation.American journal of physiology. Cell physiology · 2025Article
- AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination of NKCC2.Cells · 2024Article
- The generation of detergent-insoluble clipped fragments from an ERAD substrate in mammalian cells.Scientific reports · 2023Article
- TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.The EMBO journal · 2023Article
- ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum.Physiological reviews · 2022Review
- Golgi Alpha1,2-Mannosidase IA Promotes Efficient Endoplasmic Reticulum-Associated Degradation of NKCC2.Cells · 2021Article
- SLC26A9 is selected for endoplasmic reticulum associated degradation (ERAD) via Hsp70-dependent targeting of the soluble STAS domain.The Biochemical journal · 2021Article
- Substrate ubiquitination retains misfolded membrane proteins in the endoplasmic reticulum for degradation.Cell reports · 2021Article
- Distinct classes of misfolded proteins differentially affect the growth of yeast compromised for proteasome function.FEBS letters · 2021Article
- The Capture of a Disabled Proteasome Identifies Erg25 as a Substrate for Endoplasmic Reticulum Associated Degradation.Molecular & cellular proteomics : MCP · 2020Article
- A novel PPARɣ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cells.Experimental & molecular medicine · 2020Article
- Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations, or stress responses.BMC biology · 2020Article
- Phosphorylation of α-dystrobrevin is essential for αkap accumulation and acetylcholine receptor stability.The Journal of biological chemistry · 2020Article
- When few survive to tell the tale: thymus and gonad as auditioning organs: historical overview.Theory in biosciences = Theorie in den Biowissenschaften · 2020Review
- Regulation of inner nuclear membrane associated protein degradation.Nucleus (Austin, Tex.) · 2019Review
- Protein quality control in the secretory pathway.The Journal of cell biology · 2019Review
- Harmonizing Experimental Data with Modeling to Predict Membrane Protein Insertion in Yeast.Biophysical journal · 2019Article
- Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases.Cold Spring Harbor perspectives in biology · 2019Review
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Authors and funding
2 authors.
Funding
Abstract
Protein homeostasis in the secretory pathway is maintained by a hierarchy of quality control checkpoints, including endoplasmic reticulum-associated degradation (ERAD), which leads to the destruction of misfolded proteins in the ER, as well as post-ER proteolysis. Although most aberrant proteins are degraded by ERAD, some misfolded proteins escape the ER and are degraded instead by lysosomal/vacuolar proteases. To date, it remains unclear how misfolded membrane proteins are selected for these different fates. Here we designed a novel model substrate, SZ*, to investigate how substrate selection is mediated in yeast. We discovered that SZ* is degraded by both the proteasome and vacuolar proteases, the latter of which occurs after ER exit and requires the multivesicular body pathway. By interrogating how various conditions affect the fate of SZ*, we also discovered that heat-shock and substrate overexpression increase ERAD targeting. These conditions also increase substrate aggregation. We next found that aggregation of the membrane-free misfolded domain in SZ* is concentration dependent, and fusion of this misfolded domain to a post-ER quality control substrate instead targets the substrate for ERAD. Our data indicate that a misfolded membrane protein with a higher aggregation propensity is preferentially retained in the ER and targeted for ERAD.
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