Heat Shock Proteins and the Stress Response

Introduction

In response to ischemia, cellular responses lead to the induction of a variety of stress proteins, included among them are the heat shock proteins (Hsps) and immediate early genes (IEGs). Hsps are a family of stress proteins thought to be involved in chaperone functions, such as protein folding, trafficking, and repair. Their expression can be constitutive or inducible depending on the family member. Constitutively expressed members exist in all cell compartments, and appear essential for development and cellular function. Inducible forms can be induced following a variety of external stress including ischemia, but were originally described following heat stress . Their induction appears to be part of an orchestrated stress response. Work over the past two decades has also established that some Hsps also function as cytoprotectants. Hsps have long been known to serve as protein chaperones in the sense that they assist in protein folding and the correct attainment of functional three-dimensional configuration, while preventing incorrect folding and protein aggregation . They have also been shown to affect cellular signaling , and have been extensively studied in the setting of cerebral ischemia and demonstrated to provide protection against both global and focal cerebral ischemia.

Heat Shock Proteins

Hsps are classified according to their molecular mass, and include Hsp100, Hsp90, Hsp70, Hsp60, Hsp40, and the small Hsp families. The best-studied class is Hsp70, the 70-kDa class that includes an inducible form also known as Hsp72, Hsp70i, or simply Hsp70. Hsp70 interacts with hydrophobic peptide segments of unstructured proteins in an ATP-dependent manner. Hsp70 also contains a C-terminal substrate-binding domain that identifies unstructured polypeptide segments, and an N-terminal ATPase domain that assists in protein folding, alternating between an ATP-bound, open state with low substrate affinity and an ADP-bound closed state with high substrate affinity . In studies of cerebral ischemia, Hsp70 was observed to be induced in brain regions that were relatively resistant to ischemic insults. Hence, the notion of a “molecular penumbra” was introduced, and raised questions as to whether this expression was an epiphenomenon of the injury, or an active participant in cell survival . Subsequent studies using strategies to increase or inhibit Hsp70 expression have consistently shown that Hsp70 protects the brain and brain cells against experimental cerebral ischemia, neurodegenerative disease models, epilepsy, and trauma. Through its chaperone properties, it has been shown to reduce protein aggregates and intracellular inclusions . Two other stress proteins studied in brain ischemia include Hsp27 and Hsp32 (also known as heme oxygenase, or HO-1) . In addition to their function in protein processing, Hsps appear to protect the brain by affecting several cell death and immune response pathways .

The Heat Shock Response

The molecular mechanism for regulation of Hsps expression depends on the activity of a unique transcription factor-heat shock factor 1 (HSF1) that can bind to the 5’promoter regions of all Hsp genes and trigger transcription . Under homeostatic conditions, Hsps are located intracellularly and are bound to HSF1 [1]. An appropriate stress, such as heat, ischemia, and other causes of accumulation of unfolded proteins leads to the dissociation of Hsps from HSF, leaving Hsps free to bind target proteins. In the stressed cell, dissociated HSF is transported to the nucleus where it is phosphorylated, possibly by protein kinase C, to form activated trimers. These trimers bind to highly conserved regulatory sequences on the heat shock gene known as heat shock elements (HSEs). Once bound to HSEs, HSFs bind to the promoter region of Hsp genes, leading to more Hsp generation . Newly generated Hsps can then bind denatured proteins and act as a molecular chaperone by contributing to repair, refolding, and trafficking of damaged proteins within the cell. Hsp90 can also influence Hsp70, since Hsp90 is bound to HSF1. When Hsp90 dissociates from HSF1, HSF1 is liberated to bind HSEs, leading to more Hsp70 induction.

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