Sorting out the trash: the spatial nature of eukaryotic protein quality control

doi:10.1016/j.ceb.2013.12.006

Current Opinion in Cell Biology

Volume 26, February 2014, Pages 139-146

https://doi.org/10.1016/j.ceb.2013.12.006 Get rights and content

Highlights

•
Spatial sequestration of misfolded proteins is an early, normal response to stress.
•
PQC compartments spatially restrict misfolded proteins thus enhancing degradation.
•
The ER acts as a dynamic network for the spatial distribution of misfolded proteins.
•
Spatial protein sequestration promotes rejuvenation of daughter cells in mitosis.
•
Altered PQC is associated with neurodegenerative disorders, cancer, and aging.

Failure to maintain protein homeostasis is associated with aggregation and cell death, and underies a growing list of pathologies including neurodegenerative diseases, aging, and cancer. Misfolded proteins can be toxic and interfere with normal cellular functions, particularly during proteotoxic stress. Accordingly, molecular chaperones, the ubiquitin-proteasome system (UPS) and autophagy together promote refolding or clearance of misfolded proteins. Here we discuss emerging evidence that the pathways of protein quality control (PQC) are intimately linked to cell architecture, and sequester proteins into spatially and functionally distinct PQC compartments. This sequestration serves a number of functions, including enhancing the efficiency of quality control; clearing the cellular milieu of potentially toxic species and facilitating asymmetric inheritance of damaged proteins to promote rejuvenation of daughter cells.

Graphical abstract

Introduction

Maintaining protein homeostasis (proteostasis) is essential for a functional cellular proteome [1, 2]. Many diseases, including Alzheimer's, Parkinson's, and Huntington's disease, are linked to accumulation of toxic misfolded proteins in aggregates and inclusions [1, 2]. In order to maintain a properly functioning proteome, the cell has an extensive cellular protein quality control (PQC) network, involving chaperones and degradative pathways, that together ensure that proteins fold correctly and if misfolded, damaged or stress-denatured, that they are cleared from the cell [3, 4, 5]. Molecular chaperones maintain the solubility of misfolded species by promoting their refolding or their degradation through the ubiquitin-proteasome system (UPS) and autophagy [6, 7, 8, 9]. Sequestration of misfolded or aggregated proteins into inclusions was initially thought to be a second line of defense when quality control failed, for instance in response to proteasomal blockade [8]. This view deserves revisiting due to recent evidence that spatial sequestration of misfolded proteins is an early and physiological feature of cellular quality control, even in healthy cells [10^••]. Several distinct PQC compartments that concentrate different types of misfolded species are integral to cellular protein homeostasis (Table 1 and partially reviewed in [11]). We here review the function and components involved in the formation and clearance of these PQC compartments, and their relevance to understand diseases associated with protein aggregation.

Section snippets

Misfolded protein species are sorted into distinct protein quality control compartments

Intracellular and extracellular inclusions containing insoluble aggregates were originally observed in brains of patients affected with late-onset neurodegenerative diseases [12]. These diseases are associated with proteins that have a high propensity to aggregate in vitro and in vivo into highly ordered beta-sheet rich aggregates called amyloids [2, 13]. Under conditions of proteasome inhibition and stress, inclusions containing non-amyloid amorphous aggregates, as well as inclusions

Functional consequences of spatial quality control

What is the function of spatially sequestering misfolded proteins in such a diverse range of compartments? Each compartment seems to be tied to a distinct fate for the misfolded protein, including refolding by a specific set of chaperones, clearance by the UPS or autophagy, or terminal sequestration from the cellular milieu. One function of PQC compartments is enhancing the efficiency of PQC by restricting the diffusion of misfolded proteins and concentrating them together with chaperones and

Molecular and cellular determinants of spatial protein quality control

Formation of PQC compartments is an active process involving chaperones, ubiquitination, as well as sorting factors interacting with cellular structures, including the nuclear membrane, the ER network and the cytoskeleton. ATP-dependent molecular chaperones of the Hsp70, Hsp90, and Hsp110 families, previously shown to be important for refolding and degradation of misfolded or stress-denatured proteins, are very important for the formation of Q-bodies and their maturation into the JUNQ (Figure 2

Implications of spatial PQC sequestration in disease pathogenesis and treatment

A better understanding of spatial quality control in healthy cells can help understand what goes wrong in diseases whose hallmark is the accumulation of protein aggregates, including Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis (ALS) and many others. Genetic mutations or unknown environmental factors lead to misfolding of specific proteins that affect different neuronal types for each of these disorders. Misfolded protein inclusions are also linked to

Conclusions and future directions

Growing evidence indicates that spatial sequestration of misfolded protein species is an early cellular response to protein misfolding and does not necessarily result from proteostatic collapse or disease. A complex picture is beginning to emerge linking cellular architecture determinants to the cellular degradation and folding systems to establish spatial quality control. Future studies will have to determine how the properties of a given misfolded protein and/or the state of a given cell lead

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

Work in the Frydman lab is supported by the NIH and a Senior Scholar Award from the Ellison Foundation to JF. WV is supported by the Marie Curie International Outgoing Fellowship Program (WV, FP7-PEOPLE-2011-IOF; contract no. [303096 FOLDEG]). ES is supported by a postdoctoral fellowship from NIH (F32NS086253-01).

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¹: These authors contributed equally to this work.

View full text

Sorting out the trash: the spatial nature of eukaryotic protein quality control

Highlights

Graphical abstract

Introduction

Section snippets

Misfolded protein species are sorted into distinct protein quality control compartments

Functional consequences of spatial quality control

Molecular and cellular determinants of spatial protein quality control

Implications of spatial PQC sequestration in disease pathogenesis and treatment

Conclusions and future directions

References and recommended reading

Acknowledgements

Curr Opin Cell Biol

Mol Cell

Prog Mol Biol Transl Sci

Arch Neurol

Nature

J Cell Biol

J Immunol

Nature

J Biol Chem

Mol Cell

Cell

Nat Rev Mol Cell Biol

J Biol Chem

Proc Natl Acad Sci USA

J Biol Chem

Neuropathol Appl Neurobiol

Genes Dev

EMBO J

Adapting proteostasis for disease intervention

Science

Protein solubility and protein homeostasis: a generic view of protein misfolding disorders

Cold Spring Harb Perspect Biol

Molecular chaperones in protein folding and proteostasis

Nature

Cellular responses to misfolded proteins and protein aggregates

Methods Mol Biol

Cellular strategies of protein quality control

Cold Spring Harb Perspect Biol

The heat shock response: systems biology of proteotoxic stress in aging and disease

Cold Spring Harb Symp Quant Biol

Spatial sequestration of misfolded proteins by a dynamic chaperone pathway enhances cellular fitness during stress

Nat Cell Biol

Cleaning up: ER-associated degradation to the rescue

Cell

Functional diversity of protein fibrillar aggregates from physiology to RNA granules to neurodegenerative diseases

Biochim Biophys Acta

Hsp42 is required for sequestration of protein aggregates into deposition sites in Saccharomyces cerevisiae

J Cell Biol

Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into huntington's disease molecular pathogenesis

J Neurosci

Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

Cell

The stress of protein misfolding: from single cells to multicellular organisms

Cold Spring Harb Perspect Biol