Role of Molecular Chaperones in Stress Response and Disease

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Many organisms regularly encounter fast-acting, highly proteotoxic stress conditions, including exposure to the physiological antimicrobial hypochlorous acid (HOCl), highly elevated temperatures or acid stress. To survive these stress conditions, they employ a class of ATP-independent, stress specific chaperones, whose posttranslational activation is tailored towards the stress conditions that require their chaperone functions. Our lab investigates four of these stress-specific chaperones; Hsp33, which is activated by oxidative disulfide bond formation to protect bacteria and eukaryotic parasites against HOCl, which is commonly produced by cells of the innate host defense; Get3, a redox-regulated Hsp33 analogue that protects yeast and likely other eukaryotes against oxidative protein damage; HdeA, which is rapidly activated by acid-induced dissociation and protects enteric bacteria against acid-stress encountered in the mammalian stomach; and mitochondrial Prdx2 from Leishmania infantum, which is a temperature-regulated chaperone that protects parasites against the sudden temperature shift as they transit from insects to warm-blooded mammals. All four of these proteins are chaperone-inactive and stably folded under non-stress conditions but are activated following very rapid, stress-induced conformational rearrangements, converting them into proteins with extensive regions of intrinsic disorder. We will now combine mutational, biochemical and high-resolution structural tools to elucidate the precise working mechanism of these proteins, testing the hypothesis that stress-induced unfolding serves to generate novel, highly flexible protein-protein interaction sites. These studies have the potential to open up a completely new perspective in chaperone research, protein folding and stress response pathways. In a separate line of research, we discovered that polyphosphate (polyP), which is a universally conserved, very abundant and ubiquitously distributed polymer, works as a highly effective protein-stabilizing scaffold. This demonstrates that protein chaperones are not the only cellular solution to deal with proteotoxic stress conditions. We found that polyP increases the thermostability of proteins by stabilizing them in a predominantly β-sheet conformation. This finding helps to explain how polyP confers resistance to stress conditions that cause protein unfolding. At the same time, it also explains how polyP acts to accelerate processes such as bacterial biofilm formation, which depend on the stabilization of amyloid-like proteins in a fibril-forming cross-β-sheet conformation. We recently realized that polyP equally accelerates fibril formation of disease-associated amyloids. This activity appears to reduce the amount of toxic oligomers and, most importantly, protects neurons against amyloid toxicity. We will now further investigate this exciting suggestion that polyP is a physiologically important cytoprotective modifier of amyloidogenic processes, and might play a role in Parkinson's disease and potentially other neurodegenerative diseases associated with amyloid formation.