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Small heat-shock proteins: important players in regulating cellular proteostasis

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Abstract

Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of post-translational modifications in sHsp chaperone function, particularly in the context of disease.

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Abbreviations

Aβ:

Amyloid β

αAc:

αA-crystallin

αBc:

αB-crystallin

αc:

α-Crystallin

ACD:

α-Crystallin domain

AD:

Alzheimer’s disease

ALS:

Amylotrophic lateral sclerosis

α-syn:

α-Synuclein

CJD:

Creutzfeldt–Jakob disease

CMT:

Charcot–Marie–Tooth disease

cryo-EM:

Cryo-electron microscopy

DRM:

Desmin-related myopathy

GAFP:

Glial acidic fibrillary protein

HMN:

Hereditary motor neuropathy

Hsp:

Heat-shock protein

MS:

Multiple sclerosis

PD:

Parkinson’s disease

PrPsc :

Prion protein

SANS:

Small-angle neutron scattering

SAXS:

Small-angle X-ray scattering

sHsp:

Small heat-shock protein

TEM:

Transmission electron microscopy

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Acknowledgements

The authors sincerely thank Dr Andrew Aquilina and Prof. Roger Truscott for valuable discussions and assistance with the preparation of this manuscript and Prof. John Clark and Dr Joy Ghosh for the co-ordinates of the αB-crystallin monomer. We also thank Prof. Justin Benesch for providing the X-ray crystal structure of the ACD and C-terminal region of αB-crystallin, and we are grateful to the anonymous reviewers for their helpful comments and suggestions. SM was supported by a Royal Society Dorothy Hodgkin Fellowship, HE is supported by an Australian Research Council Future Fellowship (FT110100586) and JC is supported by a National Health and Medical Research Council Project Grant (#1068087).

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Authors and Affiliations

  1. Graduate School of Medicine, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia

    Teresa M. Treweek

  2. Illawarra Health and Medical Research Institute, Northfields Avenue, Wollongong, NSW, 2522, Australia

    Teresa M. Treweek & Heath Ecroyd

  3. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

    Sarah Meehan

  4. School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia

    Heath Ecroyd

  5. Research School of Chemistry, The Australian National University, Acton, ACT, 2601, Australia

    John A. Carver

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  1. Teresa M. Treweek
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  2. Sarah Meehan
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Correspondence to Teresa M. Treweek, Heath Ecroyd or John A. Carver.

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Treweek, T.M., Meehan, S., Ecroyd, H. et al. Small heat-shock proteins: important players in regulating cellular proteostasis. Cell. Mol. Life Sci. 72, 429–451 (2015). https://doi.org/10.1007/s00018-014-1754-5

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  • DOI: https://doi.org/10.1007/s00018-014-1754-5

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