Protein quality control in the nucleus

https://doi.org/10.1016/j.ceb.2016.03.002Get rights and content

The nucleus is the repository for the eukaryotic cell's genetic blueprint, which must be protected from harm to ensure survival. Multiple quality control (QC) pathways operate in the nucleus to maintain the integrity of the DNA, the fidelity of the DNA code during replication, its transcription into mRNA, and the functional structure of the proteins that are required for DNA maintenance, mRNA transcription, and other important nuclear processes. Although we understand a great deal about DNA and RNA QC mechanisms, we know far less about nuclear protein quality control (PQC) mechanisms despite that fact that many human diseases are causally linked to protein misfolding in the nucleus. In this review, we discuss what is known about nuclear PQC and we highlight new questions that have emerged from recent developments in nuclear PQC studies.

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.

References (110)

  • F. Eisele et al.

    Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1

    FEBS Lett

    (2008)
  • N.B. Nillegoda et al.

    Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins

    Mol Biol Cell

    (2010)
  • Z. Wang et al.

    Quality control of a transcriptional regulator by SUMO-targeted degradation

    Mol Cell Biol

    (2009)
  • P. Carvalho et al.

    Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins

    Cell

    (2006)
  • A. Khmelinskii et al.

    Protein quality control at the inner nuclear membrane

    Nature

    (2014)
  • A. Shiber et al.

    Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting

    Mol Biol Cell

    (2013)
  • S.H. Park et al.

    PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone

    Cell

    (2013)
  • J.A. Johnston et al.

    Aggresomes: a cellular response to misfolded proteins

    J Cell Biol

    (1998)
  • S.B. Miller et al.

    Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

    EMBO J

    (2015)
  • D. Kaganovich et al.

    Misfolded proteins partition between two distinct quality control compartments

    Nature

    (2008)
  • A. Janer et al.

    PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins

    J Cell Biol

    (2006)
  • S. Waelter et al.

    Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation

    Mol Biol Cell

    (2001)
  • C.K. Bailey et al.

    Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy

    Hum Mol Genet

    (2002)
  • B.H. Toyama et al.

    Identification of long-lived proteins reveals exceptional stability of essential cellular structures

    Cell

    (2013)
  • R. Kawai et al.

    Direct evidence for the intracellular localization of Hsp104 in Saccharomyces cerevisiae by immunoelectron microscopy

    Cell Stress Chaperones

    (1999)
  • Z.S. Chughtai et al.

    Starvation promotes nuclear accumulation of the hsp70 Ssa4p in yeast cells

    J Biol Chem

    (2001)
  • Y. Xie et al.

    SUMO-independent in vivo activity of a SUMO-targeted ubiquitin ligase toward a short-lived transcription factor

    Genes Dev

    (2010)
  • A. Aguzzi et al.

    Protein aggregation diseases: pathogenicity and therapeutic perspectives

    Nat Rev Drug Discov

    (2010)
  • Y.E. Kim et al.

    Molecular chaperone functions in protein folding and proteostasis

    Annu Rev Biochem

    (2013)
  • C. Park et al.

    Selective autophagy: talking with the UPS

    Cell Biochem Biophys

    (2013)
  • W.D. Heyer

    Regulation of recombination and genomic maintenance

    Cold Spring Harb Perspect Biol

    (2015)
  • E.K. Fredrickson et al.

    Exposed hydrophobicity is a key determinant of nuclear quality control degradation

    Mol Biol Cell

    (2011)
  • J.C. Rosenbaum et al.

    Disorder targets misorder in nuclear quality control degradation: a disordered ubiquitin ligase directly recognizes its misfolded substrates

    Mol Cell

    (2011)
  • E.K. Fredrickson et al.

    Substrate recognition in nuclear protein quality control degradation is governed by exposed hydrophobicity that correlates with aggregation and insolubility

    J Biol Chem

    (2013)
  • C.J. Guerriero et al.

    Hsp70 targets a cytoplasmic quality control substrate to the san1p ubiquitin ligase

    J Biol Chem

    (2013)
  • R. Prasad et al.

    A nucleus-based quality control mechanism for cytosolic proteins

    Mol Biol Cell

    (2010)
  • R. Prasad et al.

    Biosynthetic mode can determine the mechanism of protein quality control

    Biochem Biophys Res Commun

    (2012)
  • N. Furth et al.

    Exposure of bipartite hydrophobic signal triggers nuclear quality control of Ndc10 at the endoplasmic reticulum/nuclear envelope

    Mol Biol Cell

    (2011)
  • D. Mijaljica et al.

    Nibbling within the nucleus: turnover of nuclear contents

    Cell Mol Life Sci

    (2007)
  • F. Meng et al.

    Compartmentalization and functionality of nuclear disorder: intrinsic disorder and protein–protein interactions in intra-nuclear compartments

    Int J Mol Sci

    (2016)
  • G. Langst et al.

    Chromatin remodelers: from function to dysfunction

    Genes (Basel)

    (2015)
  • E. Grossman et al.

    Functional architecture of the nuclear pore complex

    Annu Rev Biophys

    (2012)
  • T. Pederson

    The persistent plausibility of protein synthesis in the nucleus: process, palimpsest or pitfall?

    Curr Opin Cell Biol

    (2013)
  • L. Chen et al.

    Degradation of specific nuclear proteins occurs in the cytoplasm in Saccharomyces cerevisiae

    Genetics

    (2014)
  • R. Schnell et al.

    Genetic and molecular characterization of suppressors of SIR4 mutations in Saccharomyces cerevisiae

    Genetics

    (1989)
  • Q. Xu et al.

    The Saccharomyces cerevisiae Cdc68 transcription activator is antagonized by San1, a protein implicated in transcriptional silencing

    Mol Cell Biol

    (1993)
  • A. Dasgupta et al.

    Sir antagonist 1 (San1) is a ubiquitin ligase

    J Biol Chem

    (2004)
  • S.G. Addinall et al.

    A genomewide suppressor and enhancer analysis of cdc13-1 reveals varied cellular processes influencing telomere capping in Saccharomyces cerevisiae

    Genetics

    (2008)
  • T. Arlow et al.

    Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

    Proc Natl Acad Sci U S A

    (2013)
  • F. Estruch et al.

    A genetic screen in Saccharomyces cerevisiae identifies new genes that interact with mex67-5, a temperature-sensitive allele of the gene encoding the mRNA export receptor

    Mol Genet Genomics

    (2009)
  • Cited by (27)

    • Chaperone-Mediated Protein Disaggregation Triggers Proteolytic Clearance of Intra-nuclear Protein Inclusions

      2020, Cell Reports
      Citation 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 Biology
      Citation 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 Neurobiology
      Citation 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).

    View all citing articles on Scopus
    View full text