Internal and External Proteotoxic Stresses in Mammalian Cells

During a number of fundamental cellular processes [protein synthesis, protein transport (to organelles), protein functioning (e.g., in subunit-subunit interactions, and organelle biosynthesis)] interactive protein surfaces are transiently exposed to the intracellular environment. This is an unavoidable internal form of stress, as improper interactions may occur against which a cell has to defend itself. When cells age or when they become genetically unstable, genetic alterations may accumulate and result in the formation of aberrant gene products; these may never fold properly during and after translation, resulting in a different and augmented form of internal stress. Finally, heritable protein folding diseases such as cystic fibrosis (CF), Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxia (SCA) cause an accumulation of damaged proteins in cells (Bailey et al. 2002; Cummings al. 1998; Kopito 1999; Wyttenbach et al. 2001) that requires the lifelong enhanced activity of chaperones, but again in a different manner, as these proteins are nonfoldable.

In this chapter, I will mainly focus on the response of cells to external forms of stress that affect the stability of proteins. The prototype of such a stress is heat shock, which can cause denaturation of proteins. Direct evidence for protein denaturation and its relevance to heat-induced lethality in mammalian cells has been, for example, provided by studies using differential scanning calorimetry

(DSC) (Lepockal. 1990,1993) and electron spin resonance (Burgman and Kon-ings 1992). Subsequent to this protein denaturation, proteins will aggregate, and a tight relation between heat-induced protein aggregation and the cell biological consequences of heat has been found (Kampinga, 1993). However, many other forms of stress such as arsenite treatment, treatment with amino acid analogs, or oxidative stress can induce (different types of) toxic protein damage. It is important to note that all forms of stress that cause some kind of protein damage also induce the heat shock response, i.e., the activation of the heat shock factor-1 that transactivates the heat-inducible chaperones (Morimoto 1998). Moreover, the induction of chaperones by one proteotoxic stress generally not only results in a transient resistance against the subsequent similar stress, but also results in cross-resistance to many, if not all, other proteotoxic stresses (Hahn and Li, 1982). In general the induced synthesis of Hsp upon stress can be viewed as an amplification of their basic chaperone function (Ellis and van der Vies 1991) and thus heat shock seems a valid model to study chaperone function and regulation in mammalian cells. Besides direct thermal effects on protein folding, heat shock also causes oxidative (protein) damage (Freeman et al. 1990), may be related to enhanced metabolic rates, which, in part, may require specialized chaperones.

It is important to note that purely genotoxic stresses such as ionizing radiation do not lead to the elevated expression of heat shock proteins (Anderson et al. 1988) and inversely, that the transiently elevated expression of heat shock proteins by, for example, heat stress does not affect the sensitivity to ionizing radiation, which is particularly relevant to the discussion on the role of Hsp in the process of apoptosis (Sect. 9).

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