Abstract
Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin–proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis and focus on its established and potential roles in renal cell physiology and pathophysiology.
Key points
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The ubiquitin–proteasome system (UPS) selectively degrades the majority of the intracellular proteins in an ATP-consuming manner and closely interacts with the autophagosomal–lysosomal system in physiological and pathophysiological situations.
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The UPS regulates important physiological processes along the entire length of nephron, including glomerular cell identity and function, erythropoiesis, glucose reabsorption and salt and water balance.
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Mutations in genes encoding enzymes of the UPS result in renal disease, and mutations in kidney-specific genes result in ubiquitin–proteasome dysfunction that leads to renal disease.
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As part of general disease processes, the UPS regulates renal fibrosis and renal inflammation, affects acute kidney injury and is involved in chronic kidney disease-associated muscle atrophy.
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Proteasomal inhibitors inhibit catalytic proteasomal subunits with differential potency and have both beneficial and disease-exacerbating effects in different pathophysiological settings.
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Specific targeting of deubiquitylating enzymes or E3 ubiquitin ligase enzymes that are involved in well-characterized disease processes will enable the development of specific new treatment options in renal disease.
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Acknowledgements
The author apologizes to all those researchers whose work could not be cited owing to space limitations. The author thanks the Deutsche Forschungsgemeinschaft (SFB 1192) and the Else Kröner Fresenius Stiftung for continuous support.
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Nature Reviews Nephrology thanks A. Cybulsky, E. Krüger and other anonymous reviewer(s) for their contribution to the peer review of this work.
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Glossary
- Endoplasmic reticulum-associated degradation (ERAD)
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A cellular pathway in which newly translated misfolded proteins of the endoplasmic reticulum are ubiquitylated and shuttled into the cytoplasm for proteasomal degradation.
- Mono-ubiquitylation
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The attachment of one ubiquitin moiety to the substrate protein.
- Polyubiquitylation
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The formation of a ubiquitin chain on a single lysine residue on the substrate protein.
- MHC class I-mediated antigen presentation
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The presentation of mostly intracellular peptides processed by the proteasome via MHC class I proteins to the immune system (cytotoxic T cells).
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Meyer-Schwesinger, C. The ubiquitin–proteasome system in kidney physiology and disease. Nat Rev Nephrol 15, 393–411 (2019). https://doi.org/10.1038/s41581-019-0148-1
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DOI: https://doi.org/10.1038/s41581-019-0148-1
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