Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes. These unexpected observations have uncovered complex layers of post-translational regulation of HSFs that integrate the metabolic state of the cell with stress biology, and in doing so control fundamental aspects of the health of the proteome and ageing.

https://www.auburn.edu/academic/classes/biol/6190/refs/L06/52400148.pdf

Heat shock factors: integrators of cell stress, development and lifespan

The long-term health of the cell is inextricably linked to protein quality control. Under optimal conditions this is accomplished by protein homeostasis, a highly complex network of molecular interactions that balances protein biosynthesis, folding, translocation, assembly/disassembly, and clearance. This review will examine the consequences of an imbalance in homeostasis on the flux of misfolded proteins that, if unattended, can result in severe molecular damage to the cell. Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks. Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregation-prone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease. The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.

/pdf/proteotoxic-stress-and-inducible-chaperone-networks-in-2duicirogo.pdf

Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging

To dampen proteotoxic stresses and maintain protein homeostasis, organisms possess a stress-responsive molecular machinery that detects and neutralizes protein damage. A prominent feature of stressed cells is the increased synthesis of heat shock proteins (Hsps) that aid in the refolding of misfolded peptides and restrain protein aggregation. Transcriptional activation of the heat shock response is orchestrated by heat shock factor 1 (HSF1), which rapidly translocates to hsp genes and induces their expression. Although the role of HSF1 in protecting cells and organisms against severe stress insults is well established, many aspects of how HSF1 senses qualitatively and quantitatively different forms of stresses have remained poorly understood. Moreover, recent discoveries that HSF1 controls life span have prompted new ways of thinking about an old transcription factor. Here, we review the established role of HSF1 in counteracting cell stress and prospect the role of HSF1 as a regulator of disease states and aging.

Regulation of HSF1 Function in the Heat Stress Response: Implications in Aging and Disease

Small heat shock proteins (sHSPs) associate with nuclei, cytoskeleton and membranes, and as molecular chaperones they bind partially denatured proteins, thereby preventing irreversible protein aggregation during stress. sHSP monomers consist of a conserved alpha-crystallin domain of approximately 90 amino acid residues, bordered by variable amino- and carboxy-terminal extensions. The sHSPs undergo dynamic assembly into mono- and poly-disperse oligomers where the rate of disassembly affects chaperoning. The alpha-crystallin domain contains several beta-strands organized into two beta-sheets responsible for dimer formation, the basic building block of most sHSPS. The amino-terminal extension modulates oligomerization, subunit dynamics and substrate binding, whereas the flexible carboxy-terminal extension promotes solubility, chaperoning and oligomerization, the latter by inter-subunit linkage. Crystallization studies have revealed sHSP structure and function. Additionally, site-directed mutagenesis, biophysical investigations, functional studies and the discovery of relationships between mutated sHSPs and diseases have illuminated the role of sHSP within cells.

Small heat shock proteins: molecular structure and chaperone function

All organisms sense and respond to environmental and physiological stress by inducing cell stress responses that protect core biosynthetic processes such as DNA repair, protein folding, and clearance of damaged proteins. Of these, the heat shock response (HSR) protects the proteome against acute exposure to elevated temperatures, oxidants, and heavy metals, for example, and to the chronic expression of metastable, aggregation-prone proteins associated with aging and diseases of protein conformation. Induction of the HSR leads to the rapid and robust expression of molecular chaperones and other cell-protective pathwaysto protect nascent chain synthesis andfolding, to prevent misfolding andaggregation, and to promote recovery from stress-induced damage. This review examines the properties of the stress-responsive transcription factor, HSF1, in the regulation of the HSR, our current understanding of the stress-sensing mechanisms that recognize and distinguish between acute stress such as heat shock and chronic proteostasis imbalance as occurs in neurodegenerative diseases, and the cell nonautonomous control of the HSR by neuronal signaling in metazoans. This complex, systems-wide interdependence ensures cellular health span and organismal life span.

/pdf/the-heat-shock-response-systems-biology-of-proteotoxic-1jpuq95ewr.pdf

The Heat Shock Response: Systems Biology of Proteotoxic Stress in Aging and Disease

Heat shock factor 2, one of the four vertebrate HSFs, transcriptional regulators of heat shock gene expression, is active during embryogenesis and spermatogenesis, with unknown functions and targets. By disrupting the Hsf2 gene, we show that, although the lack of HSF2 is not embryonic lethal, Hsf2(-/-) mice suffer from brain abnormalities, and meiotic and gameto genesis defects in both genders. The disturbances in brain are characterized by the enlargement of lateral and third ventricles and the reduction of hippocampus and striatum, in correlation with HSF2 expression in proliferative cells of the neuroepithelium and in some ependymal cells in adults. Many developing spermatocytes are eliminated via apoptosis in a stage-specific manner in Hsf2(-/-) males, and pachytene spermatocytes also display structural defects in the synaptonemal complexes between homologous chromosomes. Hsf2(-/-) females suffer from multiple fertility defects: the production of abnormal eggs, the reduction in ovarian follicle number and the presence of hemorrhagic cystic follicles are consistent with meiotic defects. Hsf2(-/-) females also display hormone response defects, that can be rescued by superovulation treatment, and exhibit abnormal rates of luteinizing hormone receptor mRNAs.

/pdf/brain-abnormalities-defective-meiotic-chromosome-synapsis-2h5npczssc.pdf

Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice

HSP25 is involved in two steps of the differentiation of PAM212 keratinocytes

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2894%2900794-2

Liliana Paslaru

Papers

Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice

HSP25 is involved in two steps of the differentiation of PAM212 keratinocytes

GRP78 induction by cyclosporin A in human HeLa cells

MAP kinase activation by cyclosporine A.

Predictive factors of glomerular filtration rate loss associated with living kidney donation: a single-center retrospective study