Medical implications of understanding the functions of human small heat shock proteins

Abstract

Small heat shock proteins (sHsps) are ubiquitous molecular chaperones that are implicated in a variety of diseases. Upon stress, they stabilize unfolding proteins and prevent them from aggregating. However, under physiological conditions without severe stress, some sHsps interact with other proteins. In a perspective view, their ability to bind specific client proteins might allow them to fine-tune the availability of the client for other, client-dependent cellular processes. Additionally, some sHsps seem to interact with specific co-chaperones. These co-chaperones are usually part of large protein machineries that are functionally modulated upon sHsps interaction. Finally, secreted human sHsps seem to interact with receptor proteins, potentially as signal molecules transmitting the stress status from one cell to another. This review focuses on the mechanistic description of these different binding modes for human sHsps and how this might help to understand and modulate the function of sHsps in the context of disease.

Keywords:

• molecular chaperone
• protein aggregation
• protein folding
• protein homeostasis
• protein–protein interaction
• small heat shock protein
• α-crystallin

Acknowledgements

Due to the journal’s restrictions in the number of references, many original papers could not be cited. We apologize for that and would like to acknowledge all the colleagues in the field for their valuable contributions. We thank Sevil Weinkauf for critical reading the manuscript.

Financial & competing interests disclosure

The authors are supported by the Deutsche Forschungsgemeinschaft (SFB 1035), CIPSM and the Peter und Traudl Engelhorn Stiftung are acknowledged for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Small heat shock proteins (HSPBs) are implicated in a variety of diseases.

• They represent a first line of defense in protein and cell homeostasis.

• They form dynamic ensembles of different, hierarchically organized oligomers.

• Human HSPBs might show four different modes of interaction with other proteins. Upon severe stress conditions they are able to promiscuously bind many cellular proteins and prevent them from aggregation. Under physiological conditions they seem to interact primarily with specific client proteins, fine-tuning the availability of the client for other, client-dependent cellular processes. Several HSPBs interact with specific co-chaperones. These co-chaperones are usually part of larger protein machineries that are functionally modulated upon HSPBs interaction. Secreted HSPBs interact with receptors and extracellular protein deposits.

• Post-translational modifications of HSPBs and hetero-oligomer formation seem to be major regulatory tools to modulate the interaction modes of HSPBs.

• Client and co-chaperone interactions seem to represent a valuable target for the development of therapeutic strategies to influence the function of HSPBs in the context of diseases. However, care has to be taken because HSPBs can promote health as well as death of cells.

• Extracellular HSPBs activate macrophages and show anti-inflammatory properties. Exploiting this function for therapies of immunological diseases seems to be on the horizon.