Protein quality control in the nucleus
Introduction
The misfolding of proteins is an unavoidable problem that every eukaryotic organelle encounters. Protein misfolding occurs via numerous mechanisms: genetic mutations, errors in transcription or translation, problems during nascent peptide folding, and stressors that damage structures of normally folded proteins. The devastating issue of protein misfolding is highlighted by the human pathologies that are causally linked to misfolded protein aggregation such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) [1]. To prevent aggregation, eukaryotic cells have evolved robust and often interconnected compartmental protein quality control (PQC) pathways that manage misfolded proteins by either refolding them into functional proteins through chaperones [2], sequestering them into large inclusions via small heat shock proteins or chaperones [2], or degrading them through the ubiquitin-proteasome system [3] or autophagy [4, 5] (Figure 1). From a historical view, much of what we have learned about eukaryotic PQC systems and their role in maintaining proteostasis has largely come from studies in the cytoplasm and endoplasmic reticulum (ER) [6]. By contrast, much less is known about PQC mechanisms in the nucleus. However, at least 15 human diseases are associated with misfolded protein aggregation in the nucleus and include Huntington's, many spinal cerebellar ataxias (SCAs), and spinal bulbar muscular atrophy (SBMA) [7].
Section snippets
Overall nuclear protein quality control
Quality control studies in the nucleus have traditionally focused on how the cell maintains the integrity of the nuclear genome and the quality of mRNA before export from the nucleus [8, 9]. By contrast, our understanding of how the cell maintains the quality of nuclear proteins has lagged behind. The protein aspect of overall nuclear quality control is exceptionally important to consider because an escalating failure to remove or repair misfolded nuclear proteins can lead to a deterioration in
PQC degradation in the nucleus
The majority of proteasomes are nuclear localized [26], and the ubiquitin–proteasome system is the main route for misfolded protein degradation in the nucleus [3]. However, a recent study has suggested that nuclear proteins destined for proteasome degradation are first exported from the nucleus and destroyed by cytoplasmic proteasomes [27]. It is not clear if this is specific to a class of proteins that contain nuclear export signals or general for all nuclear proteins. However, it is clear
PQC chaperones in the nucleus
A common characteristic amongst nuclear PQC ubiquitin ligases is that chaperones have been implicated in the degradation of some substrates [15•, 16••, 17••, 19••, 42•, 44, 53, 54, 55]. A few reports demonstrate that chaperones are required for the ubiquitination of misfolded cytoplasmic proteins destined for nuclear PQC degradation by San1 [15•, 16••, 17••]. Another study showed that ubiquitination via San1 does not universally require chaperones [12••]. This is a controversial aspect of
PQC inclusions in the nucleus
Although each cellular compartment possesses a robust complement of folding and degradative PQC activities, the burden of misfolded proteins can exceed the capacity of the compartment's PQC systems during stress or with age [59, 60, 61]. When the burden of misfolded proteins overwhelms a compartment's PQC pathways, misfolded proteins can aggregate [59, 60, 61]. One way the cell counters the incapacity of PQC pathways is to concentrate misfolded proteins into inclusion bodies that sequester
PQC interplay between the nucleus and cytoplasm
Finally, it is important to consider that there will likely be significant interplay between nuclear and cytoplasmic PQC pathways as there is an intimate and dynamic communication between the two compartments through the nuclear pore. One interesting type of PQC interplay that has emerged in the last few years is that misfolded proteins are not always excluded from the nucleus if they are first generated in the cytoplasm [15•, 16••, 17••, 18•]. This seems counterintuitive because cytoplasmic
Concluding remarks
We have gained foundational knowledge about nuclear PQC during the last decade. However, important pieces are still missing from the nuclear PQC puzzle. For example, it is not yet known if there is a mammalian equivalent to yeast San1. In addition, nuclear PQC functions for the mammalian homologs of yeast Doa10 and Ubr1 have yet to be shown. It will also be crucial to determine the particular features of misfolded proteins that are recognized by individual nuclear PQC degradation pathways, and
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We tried our best to cite all primary literature pertaining specifically to nuclear PQC. We apologize to our colleagues if we unintentionally missed their relevant studies due to space constrictions. This work was supported by a NIH/NIGMS training Grant 5T32 GM007750 to R.D.J. and a NIH/NIA Grant R01 AG031136 to R.G.G.
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Cited by (27)
Nuclear protein quality control in yeast: The latest INQuiries
2022, Journal of Biological ChemistryChaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions
2020, Cell ReportsCitation Excerpt :Thus, it is important to understand the machineries and mechanisms that act in the nucleus to maintain proteostasis. The use of model proteins targeted to the nucleus has uncovered quality control mechanisms resulting in the degradation of misfolded proteins or their sequestration into inclusions (Jones and Gardner, 2016; Sontag et al., 2017). Studies in the yeast Saccharomyces cerevisiae identified ubiquitin ligases that recognize misfolded proteins and mediate their proteasomal degradation.
Progesterone induced Warburg effect in HEK293 cells is associated with post-translational modifications and proteasomal degradation of progesterone receptor membrane component 1
2019, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :MG132 acts primarily on the chymotrypsin-like site in the β-subunit of 20S proteasome [79]. Alternatively it is possible that p100 is degraded by the nuclear autophagy pathway [80,81] which has been shown to mediate degradation of nuclear lamina components in mammals [82,83]. Upon oncogenic insults, a nuclear pool of the autophagy protein has been shown to interact with nuclear lamina protein - lamin B1 at heterochromatin regions and mobilize chromatin associated lamin B1 into the cytoplasm for degradation via autophagy, which reinforces senescence [84,85].
Progressing neurobiological strategies against proteostasis failure: Challenges in neurodegeneration
2017, Progress in NeurobiologyCitation Excerpt :In order to properly regulate the expression of genetic material, the state of proteostasis inside nucleus becomes an obvious requisite for a cell. Although, as compared to cytoplasm and endoplasmic reticulum the understanding of proteostasis mechanism in nucleus is lacking (Jones and Gardner, 2016). According to current understanding, mostly nuclear proteins are synthesized and imported from cytoplasm through nuclear pores, which is expandable and aqueous in nature (Gallagher et al., 2014).