Ability Of Heat Shock Proteins Research Articles

Heat Shock Proteins in the Regulation of the Apoptotic Response

Cell growth, differentiation and death are highly regulated events during the normal development of cells. Following the pioneering work of Kerr [1], it has become apparent that dying eukaryotic cells can undergo two fundamentally different types of death, necrosis or accidental cell death, and apoptosis or programmed cell death. Apoptosis, unlike necrosis, occurs through the activation of a cell-intrinsic death cascade which can be modulated by many exogenous signals. The dying cell undergoes a relatively ordered form of cell death characterised morphologically by cytoplasmic shrinkage, cellular crenation, nuclear margination and condensation, internucleosomal DNA fragmentation and ~nally formation of apoptotic bodies [2–5]. A critical part of apoptosis is the ef~cient recognition and removal of these cells by tissue macrophages without an in_ammatory response [6]. This involves the rearrangement and biochemical alteration of the plasma membrane in the dying cell aiding recognition of the apoptotic cell by macrophages [7]. This mechanism prevents the release of the cytotoxic contents of apoptotic proin_ammatory cells and limits the possibility of neighbouring host cell injury [8]. The apoptotic process is fundamentally distinct from cell death by necrosis or lysis where cells release their contents into the surrounding tissues and perpetuate the local in_ammatory response. Apoptosis plays an essential part in normal tissue homeostasis with important roles in embryological remodelling, in_ammation, and immune tolerance [2,9,10]. Dysregulated apoptosis is associated with a variety of human diseases, including cancer, autoimmunity, viral infections, allergic disorders and neurodegenerative diseases [5,11,12]. Heat shock proteins (HSPs) are stress response proteins found in all species which are thought to play a protective role in cells under stress [13,14]. Recent evidence supports a role for HSPs in modulating a cell’s response to an apoptotic stimulus. In general, HSPs have been shown to protect cells from an apoptotic inducing signal [15]. Cells exposed to ever increasing increments of a noxious stressor respond generally in a graded manner [16]. Low stress levels appear to induce HSPs altering cellular biochemistry to promote survival at levels of environmental stress which otherwise may be lethal to the cell. This graded resistance is kinetically linked to the synthesis of HSPs [17]. When the inducing stress is removed these cells continue to function normally and HSP levels return to normal. As stress levels increase cellular damage exceeds the protective ability of HSPs and programmed cell death or apoptosis is triggered. At extremes of environmental stress the cell is no longer capable of controlling its fate, and necrosis or degenerative cell death becomes the predominant form of cell death. This view of the universal cellular protective effect of HSPs has, however, recently come under challenge with the revelation that HSPs can, depending on the cell type and stimulus evoked, induce increased apoptosis [18,19,20]. A better understanding of the heat shock response, with speci~c regard to the apoptotic effect of HSPs, may provide important insight into the regulation of apoptosis and may suggest paradigms for therapeutic interventions into diseases where dysregulated apoptosis occurs.

Heat-shock proteins as molecular chaperones.

Functional proteins within cells are normally present in their native, completely folded form. However, vital processes of protein biogenesis such as protein synthesis and translocation of proteins into intracellular compartments require the protein to exist temporarily in an unfolded or partially folded conformation. As a consequence, regions buried when a polypeptide is in its native conformation become exposed and interact with other proteins causing protein aggregation which is deleterious to the cell. To prevent aggregation as proteins become unfolded, heat-shock proteins protect these interactive surfaces by binding to them and facilitating the folding of unfolded or nascent polypeptides. In other instances the binding of heat-shock proteins to interactive surfaces of completely folded proteins is a crucial part of their regulation. As heat shock and other stress conditions cause cellular proteins to become partially unfolded, the ability of heat-shock proteins to protect cells against the adverse effects of stress becomes a logical extension of their normal function as molecular chaperones.