Role of the heat-shock response in the life and death of proteins.

Abstract

Changes in protein levels and the folded states of proteins are sensed by molecular chaperones and the degradative machinery that function to maintain cellular protein homeostasis. The importance of these systems is highlighted by their high degree of functional and structural conservation across evolution, from prokaryotes to eukaryotes, and their essential roles in a variety of cellular functions. The chaperone network, proteases, and components of the degradative machinery are also linked by common genetic regulatory pathways. For example, many of the proteins involved in protein folding and degradation are also heat-shock proteins whose expression is induced when cells are stressed and accumulate denatured or malfolded proteins. The family of heat-shock proteins (HSPs) encompasses a number of functionally related proteins that are expressed constitutively and/or at elevated levels upon exposure of cells to a variety of stress conditions including elevated temperature, arsenite, heavy metals, amino acid analogues, and oxidants. The chaperones and proteolytic systems often function together to determine the ultimate fates of proteins and are often coordinately regulated, as outlined in FIGURE 1. The heat-shock response regulates proteolysis by enhancing the expression of proteolytic factors and proteases, as well as of chaperones which may function as cofactors for proteolysis. The stress response in both prokaryotes and eukaryotes is, in turn, regulated by the proteolytic machinery (also A. Mathew, S. K. Mathur, and R. I. Morimoto, unpublished observations). This review will address the chaperone requirements in eukaryotic proteolysis and the regulation of eukaryotic chaperone expression by the ubiquitin–proteasome proteolytic system. A number of recent reviews have also addressed chaperone activities associated with proteolysis in prokaryotes and eukaryotes.