Heat shock proteins and their role in human diseases

Elevated expression of heat shock proteins (HSPs) has been demonstrated following various forms of stress, such as heat, heavy metal or ethanol treatment, hypoxia, ischemia, and they are also upregulated in several diseases and infections, as their most important function is to protect cells from the harmful effects of stress. As molecular chaperones they regulate the biosynthesis, folding/unfolding, transport and assembly of cellular proteins. Following cellular stress, they protect uncorrectly folded proteins against aggregation, facilitate the refolding of misfolded proteins. In addition, these proteins also can assist in the proteasomal degradation of peptides that cannot be refolded. They also have crucial role in membrane quality control by binding to lipid rafts maintaining the membrane stability during stress conditions. Moreover, HSPs can inhibit certain steps of the apoptotic pathway and they also can decrease the damaging effect of oxidative stress. These properties enable them to have protective effects in different pathological conditions. Here, we summarize our current view on the role of HSPs in human diseases like myocardial infarction, ischemic stroke, different neurodegenerative disorders, diabetes or cancer. Acta Biol Szeged 59(Suppl.1):121-141 (2015) Key wordS cancer diabetes ethanol toxicity HSP families ischemia/reperfusion neurodegeneration Submitted Jan 6, 2015; Accepted April 28, 2015 *Corresponding author. E-mail: [email protected] 121 Heat shock proteins Heat shock proteins (HSPs), also called stress proteins, are ubiquitously expressed, evolutionarily conserved chaperone proteins. The first observation of the heat shock response was the discovery of heat-induced chromosomal puffings on the Drosophila buscii salivary gland chromosomes (Ritossa 1962). Later it was observed that heat shock treatment led to the synthesis of new proteins that were similar in different tissues of Drosophila melanogaster, while the levels of other proteins were reduced (Tissieres et al. 1974). A number of specific proteins, called HSPs were later identified that are upregulated in different types of organisms in response to elevated temperature. It subsequently turned out that not only heat shock, but other stressors too can induce the expression of HSPs and they are therefore also called stress proteins. They can be induced by various forms of stress, such as heat, heavy metal or ethanol treatment, hypoxia, ischemia, and the genes of these proteins are also upregulated in several diseases and infections. HSPs are rapidly induced in response to cellular stress because their most important function is to protect cells from the harmful effects of stress. The synthesis of HSPs contributes to the development of a transient thermotolerance. A mild, sublethal heat-stress can induce the expression of HSPs and increase cell survival after a subsequent, normally lethal heat treatment. This phenomenon, called preconditioning, is observed in different cell types and tissues. Other stress factors such as hypoxia or ethanol treatment also can enhance HSP expression and transient stress resistance. Interestingly, thermotolerance is also induced when the initial heat-treatment drastically suppresses total protein synthesis (Li and Werb 1982). Under heat shock conditions overall protein synthesis is reduced, while HSP mRNA and protein synthesis is increased in the first few hours of hyperthermia (Hickey and Weber 1982). At high temperatures some steps of protein synthesis, such as RNA splicing, are inhibited. Compensating, HSP RNAs often do not contain introns (Csermely and Yahara 2002). Most of the stress-induced proteins are molecular chaperones, that mediate the correct folding and assembly of other proteins, but they are not a component of the final structures (Ellis 1990). Recently, the term “proteostasis’ is used to describe the function of chaperones controling protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation (Powers et al. 2009). They also participate in antigen presentation by chaperoning and transferring antigenic peptides (Li et al. 2002). Some HSPs, especially members of the HSPC (HSP90) family, are also implicated in different signal transduction pathways (Csermely et al. 1998). During stress conditions partially denatured, misfolded proteins accumulate and their exposed hydrophobic regions