Function And Regulation Of Heat Shock Response
Proteins are the primary functional molecules of any living organism as well as its building blocks, thus proteostasis is the basis for normal organismal function. The function of the protein depends on its tertiary structure, which is pre-determined by the order and properties of amino acids it is made of, which is in turn derived from the DNA sequence of the gene encoding the protein, as well as a degree of flexibility. This physical duality of proteins means they can exist in their active form only in a very narrow environmental profile. Even seemingly slight deviations from the optimum conditions, will lead to consequent denaturation, aggresome and stress induced nuclear granule formation and loss or disruption of protein, and consequentially, cellular function. One of the cellular mechanisms devised to mediate and prevent further proteome damage and the theme of this essay is Heat Shock Response (HSR).
HSR is classically understood as induced expression of heat shock proteins (HSPs) following a heat shock (HS), which, contrary to the name, can be any rapid stress fluctuations, not necessarily those of temperature. However, recent research suggests the scope of the response is much wider and includes both transcriptional induction and repression of several distinct gene classes and their protein products.
HSR is thought to be triggered by increased proteotoxicity instead of environmental change detection. Increased plasma membrane fluidity due to energy absorption in the lipid component of bilayer and aggregation of membrane bound proteins may be another factor involved in triggering HSR (Torok, et al. , 2003). Induction of HSR results in a large-scale transcriptional response, for example, in mammals, the expression of 10% of all active genes is upregulated and roughly half is downregulated (Mahat, et al. , 2016). There are 7 upregulated protein classes: HSPs, regulatory proteins, cytoskeleton associated proteins, proteins involved in proteolysis, nucleic acid repairing proteins, metabolic enzymes and transport and membrane modulating proteins. The exact relative abundance of each gene class differs between organisms depending on individual cellular environment and needs. Repressed genes may be gradually downregulated from the onset of the HSR or with a delay, both mechanisms appear to be unrelated as histone modification profiles differ. Genes downregulated from the get-go are generally concerned with lowering the metabolic activity of the cell to allocate more energy for ATP dependant HSR processes. Delayed inhibition of genes is caused by the upregulated regulatory proteins as a measure for further energy conservation and minimisation of damage.
First to be initiated and the front line of HSR is HSF1 induced HSP expression. HSPs are a subgroup of chaperone proteins which are proteins able of discriminate denaturated protein based on increased exposure of hydrophobic regions and then, following reversable ATP-dependant binding of the protein, aid correct polypeptide folding by either preventing inappropriate binding of other molecules in case of holdases or by undergoing a conformational change which physically folds the bound polypeptide in case of foldases.
Correct folding of the bound protein lowers the affinity of the chaperone for it and thus triggers disassociation. There are 5 distinct chaperone families relevant to HSR– Hsp100s (hexameric unfoldases), Hsp90s (large complex of proteins), Hsp70s (system of 2 cochaperones), Hsp60s (the number is indicative of their molecular weight) and sHsps (oligomeric). Most HSPs are ubiquitously expressed in absence of HS and highly conserved across different domains of life due to their function being a requirement for proteostasis, however their expression is greatly boosted as a part of HSR. HSP transcription is initiated by heat shock transcription factor 1 (HSF1). HSF1 is constitutively expressed as a monomer and, under normal circumstances of little denaturated protein, is inactive due to being bound by solely Hsp70s or Hsps70s and Hsp90s. Following HS, the bound HSPs temporarily disengage from HSF1 monomers due to increase in stoichiometric proportion of denaturated protein outcompeting HSF1 as HSP substrate, allowing HSF1 to assume its active trimer configuration and bind HS elements (HSE) located at HSP promoters.
HSF1 transcriptional activity is finetuned by integrating feedback from various cellular systems via independent post-translational modifications: phosphorylation of serine and threonine residues, carried out by various kinase signalling cascades, slightly ups transcriptional activity of HSF1 by granting greater heat resistance while re-binding of HSPs, indicative of the extent of proteome denaturation, decreases it.
