Abstract
In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins are prone to aggregate, cells have evolved several elaborate quality control systems to deal with these potentially toxic proteins. First, various molecular chaperones will seize the misfolded protein and either attempt to refold the protein or target it for degradation via the ubiquitin-proteasome system. The degradation of misfolded proteins is clearly compartmentalized, so unique degradation pathways exist for misfolded proteins depending on whether their subcellular localization is ER/secretory, mitochondrial, cytosolic or nuclear. Recent studies, mainly in yeast, have shown that the nucleus appears to be particularly active in protein quality control. Thus, specific ubiquitin-protein ligases located in the nucleus, target not only misfolded nuclear proteins, but also various misfolded cytosolic proteins which are transported to the nucleus prior to their degradation. In comparison, much less is known about these mechanisms in mammalian cells. Here we highlight recent advances in our understanding of nuclear protein quality control, in particular regarding substrate recognition and proteasomal degradation.
Highlights
As a result of cellular stress, genomic mutations or defects in transcription, translation, intracellular trafficking or association with other macromolecules, cells continuously produce misfolded proteins.All cells have evolved various measures to cope with the presence of such partially denatured proteins
The significant contribution of nuclear protein quality control to overall cellular proteostasis is demonstrated by the fact that cytosolic quality control substrates are transferred to the nucleus for degradation
While it seems to be clear that this shuttling mechanism is mediated by chaperones and co-chaperones, the mechanism that decides whether a substrate remains in the cytosol or is transported to the nucleus, is still not clear
Summary
As a result of cellular stress, genomic mutations or defects in transcription, translation, intracellular trafficking or association with other macromolecules, cells continuously produce misfolded proteins. To avoid the hazard of misfolded proteins forming intracellular aggregates, the cellular quality control systems appear to follow a better-safe-than-sorry principle, and are prone to target proteins which are structurally perturbed, but still functional. In eukaryotic cells most proteins are degraded via the ubiquitin-proteasome system (UPS) [9] In this pathway, the specificity is ensured by labeling substrates with a chain of ubiquitin moieties. Data, primarily from yeast, suggest that certain misfolded cytosolic proteins are transported to the nucleus for degradation [27] (Figure 1) Whether this is a common mechanism in mammals is still not clear. In the following we will review protein quality control, E3s (Table 1) and degradation mechanisms in the nucleus
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