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Heat‐Shock Protein Regulation of Protein Folding, Protein Degradation, Protein Function, and Apoptosis

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Handbook of Neurochemistry and Molecular Neurobiology

Abstract:

Heat‐shock proteins (Hsps), induced by heat and other stresses via heat‐shock factor (HSF) actions on heat‐shock elements (HSEs) in Hsp promoters, bind to and regulate other proteins. Hsc70 regulates folding while proteins are being synthesized on the ribosome and chaperones proteins to intracellular organelles. Hsp70, in combination with cochaperones Hip and Hop, refolds partially denatured proteins. Hsp70, in combination with cochaperones BAG‐1 and CHIP, targets proteins for degradation in the proteasome. Hsp90 chaperones proteins—including HSF, estrogen receptor, and NOS—to regulate their availability and function. The mitochondrial Hsp70 (mtHsp70), together with cochaperones, facilitates protein/peptide entry into mitochondria. Hsps also play major roles in regulating apoptosis. Hsp70 modulates mitochondrial‐caspase‐3‐dependent apoptosis by binding apoptotic protease activation factor‐1 (Apaf‐1) and disrupting the formation of the Apaf‐1/cytochrome c/caspase‐9 apoptosome, which prevents activation of caspase‐3. Hsp70 binds AIF to prevent mitochondrial‐mediated, caspase‐independent apoptosis. JNK phosphorylation and acts upstream of the mitochondria to prevent stress‐mediated mitochondrial‐induced apoptosis. The expression of Hsp70 and other Hsps is generally protective as Hsp70 transgenic mice and viral overexpression of Hsps protect neurons, brain, and cells against ischemia and other types of injury. However, Hsp70 facilitates TNF‐mediated cell death via the extrinsic apoptotic pathway by binding IKKγ and preventing activation of NF‐κB signaling that promotes caspase‐8 activation of caspase‐3 and leads to cell death. Coincident TNF receptor activation and Hsp70 expression is lethal to the cell. The mtHsp60 and Hsp10 protect against protein aggregation and refold denatured proteins; but when released from mitochondria also activate caspase‐3 and produce apoptosis. Thus, Hsps promote proper protein folding and protein refolding, disaggregate proteins and chaperone proteins across membranes; or they can target proteins for degradation and even stimulate cell apoptosis.

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Acknowledgments

This chapter has relied heavily upon the summaries of many recent reviews on various aspects of Hsp function. The authors regret not citing most of the primary references to the large amount of information covered in this brief review. This review was supported in part by grants from the NIH/NINDS that funded various aspects of the authors’ own work in this area.

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  1. R. Ran
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  2. A. Lu
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  3. H. Xu
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  4. Y. Tang
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  5. F. R. Sharp
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, 10962, Orangeburg, Newyork, USA

    Abel Lajtha (Director) (Director)

  2. Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, 94305-5487, USA

    Pak H. Chan (Director Neurosurgical Labouratories) (Director Neurosurgical Labouratories)

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Ran, R., Lu, A., Xu, H., Tang, Y., Sharp, F.R. (2007). Heat‐Shock Protein Regulation of Protein Folding, Protein Degradation, Protein Function, and Apoptosis. In: Lajtha, A., Chan, P.H. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, New York, NY. https://doi.org/10.1007/978-0-387-30383-3_6

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