Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, ...including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.
Prions are an unusual form of epigenetics: Their stable inheritance and complex phenotypes come about through protein folding rather than nucleic acid-associated changes. With intimate ties to ...protein homeostasis and a remarkable sensitivity to stress, prions are a robust mechanism that links environmental extremes with the acquisition and inheritance of new traits.
HSP90 and the chaperoning of cancer Whitesell, Luke; Lindquist, Susan L
Nature reviews. Cancer,
10/2005, Letnik:
5, Številka:
10
Journal Article
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Standing watch over the proteome, molecular chaperones are an ancient and evolutionarily conserved class of proteins that guide the normal folding, intracellular disposition and proteolytic turnover ...of many of the key regulators of cell growth, differentiation and survival. This essential guardian function is subverted during oncogenesis to allow malignant transformation and to facilitate rapid somatic evolution. Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
How can species remain unaltered for long periods yet also undergo rapid diversification? By linking genetic variation to phenotypic variation via environmental stress, the Hsp90 protein-folding ...reservoir might promote both stasis and change. However, the nature and adaptive value of Hsp90-contingent traits remain uncertain. In ecologically and genetically diverse yeasts, we find such traits to be both common and frequently adaptive. Most are based on preexisting variation, with causative polymorphisms occurring in coding and regulatory sequences alike. A common temperature stress alters phenotypes similarly. Both selective inhibition of Hsp90 and temperature stress increase correlations between genotype and phenotype. This system broadly determines the adaptive value of standing genetic variation and, in so doing, has influenced the evolution of current genomes.
For a protein to function appropriately, it must first achieve its proper conformation and location within the crowded environment inside the cell. Multiple chaperone systems are required to fold ...proteins correctly. In addition, degradation pathways participate by destroying improperly folded proteins. The intricacy of this multisystem process provides many opportunities for error. Furthermore, mutations cause misfolded, nonfunctional forms of proteins to accumulate. As a result, many pathological conditions are fundamentally rooted in the protein-folding problem that all cells must solve to maintain their function and integrity. Here, to illustrate the breadth of this phenomenon, we describe five examples of protein-misfolding events that can lead to disease: improper degradation, mislocalization, dominant-negative mutations, structural alterations that establish novel toxic functions, and amyloid accumulation. In each case, we will highlight current therapeutic options for battling such diseases.
Self‐templating amyloid forms of Sup35 constitute the yeast prion PSI+. How the protein‐remodelling factor, Hsp104, collaborates with other chaperones to regulate PSI+ inheritance remains poorly ...delineated. Here, we report how the Ssa and Ssb components of the Hsp70 chaperone system directly affect Sup35 prionogenesis and cooperate with Hsp104. We identify the ribosome‐associated Ssb1:Zuo1:Ssz1 complex as a potent antagonist of Sup35 prionogenesis. The Hsp40 chaperones, Sis1 and Ydj1, preferentially interact with Sup35 oligomers and fibres compared with monomers, and facilitate Ssa1 and Ssb1 binding. Various Hsp70:Hsp40 pairs block prion nucleation by disassembling molten oligomers and binding mature oligomers. By binding fibres, Hsp70:Hsp40 pairs occlude prion recognition elements and inhibit seeded assembly. These inhibitory activities are partially relieved by the nucleotide exchange factor, Fes1. Low levels of Hsp104 stimulate prionogenesis and alleviate inhibition by some Hsp70:Hsp40 pairs. At high concentrations, Hsp104 eliminates Sup35 prions. This activity is reduced when Ssa1, or enhanced when Ssb1, is incorporated into nascent prions. These findings illuminate several facets of the chaperone interplay that underpins PSI+ inheritance.
Under proteotoxic stress, some cells survive whereas others die. The mechanisms governing this heterogeneity in cell fate remain unknown. Here we report that condensation and phase transition of ...heat-shock factor 1 (HSF1), a transcriptional regulator of chaperones
, is integral to cell-fate decisions underlying survival or death. During stress, HSF1 drives chaperone expression but also accumulates separately in nuclear stress bodies called foci
. Foci formation has been regarded as a marker of cells actively upregulating chaperones
. Using multiplexed tissue imaging, we observed HSF1 foci in human tumours. Paradoxically, their presence inversely correlated with chaperone expression. By live-cell microscopy and single-cell analysis, we found that foci dissolution rather than formation promoted HSF1 activity and cell survival. During prolonged stress, the biophysical properties of HSF1 foci changed; small, fluid condensates enlarged into indissoluble gel-like arrangements with immobilized HSF1. Chaperone gene induction was reduced in such cells, which were prone to apoptosis. Quantitative analysis suggests that survival under stress results from competition between concurrent but opposing mechanisms. Foci may serve as sensors that tune cytoprotective responses, balancing rapid transient responses and irreversible outcomes.
Protein misfolding, whether caused by aging, environmental factors, or genetic mutations, is a common basis for neurodegenerative diseases. The misfolding of proteins with abnormally long ...polyglutamine (polyQ) expansions causes several neurodegenerative disorders, such as Huntington's disease (HD). Although many cellular pathways have been documented to be impaired in HD, the primary triggers of polyQ toxicity remain elusive. We report that yeast cells and neuron-like PC12 cells expressing polyQ-expanded huntingtin (htt) fragments display a surprisingly specific, immediate, and drastic defect in endoplasmic reticulum (ER)-associated degradation (ERAD). We further decipher the mechanistic basis for this defect in ERAD: the entrapment of the essential ERAD proteins Npl4, Ufd1, and p97 by polyQ-expanded htt fragments. In both yeast and mammalian neuron-like cells, overexpression of Npl4 and Ufd1 ameliorates polyQ toxicity. Our results establish that impaired ER protein homeostasis is a broad and highly conserved contributor to polyQ toxicity in yeast, in PC12 cells, and, importantly, in striatal cells expressing full-length polyQ-expanded huntingtin.
In mammals, the cytoprotective heat-shock response is regulated primarily by heat shock factor 1 (HSF1). Unfortunately, the effects of HSF1 also support the ability of cancer cells to accommodate ...imbalances in signaling and alterations in DNA, protein and energy metabolism associated with oncogenesis. The malignant lifestyle confers dependence on this 'non-oncogene', suggesting a therapeutic role for HSF1 inhibitors.
We begin with an overview of how HSF1 affects cancer biology and how its activity is regulated. We then summarize progress in discovery and development of HSF1 inhibitors, their current limitations and potential as anticancer agents with a fundamentally different scope of action from other clinically validated modulators of protein homeostasis.
It is likely that within the next 5 years usable inhibitors of HSF1 will be identified and in early pre-clinical evaluation.
Self-perpetuating changes in the conformations of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture and conformational conversion of ...amyloids remain poorly understood. Amyloid conformers of Sup35 are the molecular embodiment of the yeast prion known as PSI, which produces heritable changes in phenotype through self-perpetuating changes in protein folding. Here we determine the nature of Sup35's cooperatively folded amyloid core, and use this information to investigate central questions in prion biology. Specific segments of the amyloid core form intermolecular contacts in a 'Head-to-Head', 'Tail-to-Tail' fashion, but the 'Central Core' is sequestered through intramolecular contacts. The Head acquires productive interactions first, and these nucleate assembly. Variations in the length of the amyloid core and the nature of intermolecular interfaces form the structural basis of distinct prion 'strains', which produce variant phenotypes in vivo. These findings resolve several problems in yeast prion biology and have broad implications for other amyloids.
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