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Cellular strategies for controlling protein aggregation

Nature Reviews Molecular Cell Biology volume 11, pages 777–788 (2010)Cite this article

Subjects

Key Points

  • Cellular systems for protein quality control act to refold or degrade misfolded proteins, thereby preventing protein aggregation. Stress conditions and ageing can lead to an exhaustion of this protective system, causing the generation of protein aggregates.

  • The structures of protein aggregates are highly variable, ranging from amorphous to highly ordered amyloid fibrils, all of them sharing an increased β-sheet content.

  • Cells control protein aggregation by directing misfolded proteins to distinct deposition sites.

  • Protein aggregates are frequently segregated in an asymmetric manner during cell division, allowing the generation of damage-free daughter cells.

  • Cells have developed different strategies to remove protein aggregates. The refolding of aggregated proteins in bacteria, yeast and plants is mediated by the cooperation of 70-kDa heat shock protein 70 (Hsp70) and Hsp104 chaperones and is facilitated by the co-aggregating of small HSPs. Aggregates can also be removed by autophagy, which is a major clearance pathway for aggregates in mammals.

Abstract

The aggregation of misfolded proteins is associated with the perturbation of cellular function, ageing and various human disorders. Mounting evidence suggests that protein aggregation is often part of the cellular response to an imbalanced protein homeostasis rather than an unspecific and uncontrolled dead-end pathway. It is a regulated process in cells from bacteria to humans, leading to the deposition of aggregates at specific sites. The sequestration of misfolded proteins in such a way is protective for cell function as it allows for their efficient solubilization and refolding or degradation by components of the protein quality-control network. The organized aggregation of misfolded proteins might also allow their asymmetric distribution to daughter cells during cell division.

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Figure 1: Overview of cellular protein aggregation.
Figure 2: Pathways for the cellular sequestration of protein aggregates.
Figure 3: Protein disaggregation by the Hsp104–Hsp70 bi-chaperone system.
Figure 4: The role of small heat shock proteins in protein aggregation.
Figure 5: A model for the selective autophagic degradation of protein aggregates.
Figure 6: Asymmetric distribution of damaged proteins as a strategy for rejuvenating the progeny.

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Acknowledgements

We would like to thank Y. Cully for figure preparation. This work was supported by grants of the Deutsche Forschungsgemeinschaft (BU617/17-1) to B.B. and A.M., and of the Network Research Heidelberg to B.B.

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  1. Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, D-69,120, Heidelberg, Germany

    Jens Tyedmers, Axel Mogk & Bernd Bukau

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Glossary

Conformer

One of many possible structural states from the same protein species.

Molecular chaperone

One of a group of unrelated proteins that interact with non-native polypeptides to assist in their folding, transport and assembly.

Heat shock protein

A protein that shows increased expression in stress conditions through a specialized heat shock-response element in the promoter of the corresponding gene.

AAA+ protease

An ATP-dependent proteolytic machinery that acts in general and regulatory proteolysis.

E3 ubiquitin ligase

A component of the ubiquitin–proteasome system that delivers activated ubiquitin moieties to special substrates and thereby provides substrate specificity for ubiquitylation.

Juxtanuclear quality-control compartment

A compartment for the deposition of soluble, misfolded proteins in yeast and mammals. The targeting of substrates to this deposition involves ubiquitylation.

Insoluble protein deposit

A perivacuolar quality-control compartment for the deposition of terminally aggregated proteins observed in yeast and mammalian cells. One group of substrate proteins accumulating here are aggregates of amyloidogenic proteins.

Ubiquitin proteasome system

A cellular quality-control system for the ubiquitin-dependent degradation of substrate proteins by the proteasome.

E2 ubiquitin-conjugating enzyme

A component of the ubiquitin proteasome system that harbours an activated ubiquitin moiety and cooperates with E3 ligases in substrate ubiquitylation.

Lys63-linked polyubiquitylation

A polyubiquitin chain in which the ubiquitin molecules are linked by the internal Lys63 residue of ubiquitin.

J protein

A co-chaperone of HSP70 chaperones that harbours a characteristic domain called a J domain and is responsible for activating the ATPase activity of HSP70.

Autophagosome

A double-membrane vesicle in the cytoplasm that includes intracellular components for lysosomal degradation.

Polarisome

A protein complex involved in determining cell polarity by directing the localized assembly of actin filaments.

Septin ring

A ring-shaped structure that forms in the division plane at the future septation site.

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Tyedmers, J., Mogk, A. & Bukau, B. Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol 11, 777–788 (2010). https://doi.org/10.1038/nrm2993

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