Proteostasis
[1][2] Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes,[3] as well as aggregation-associated degenerative disorders.
[5] Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostatic perturbations from pathogens such as viruses.
Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded proteome.
[7] At the same time, the exit channel prevents premature folding by impeding large scale interactions within the peptide chain that would require more space.
[8] They recognize exposed segments of hydrophobic amino acids in the nascent peptide chain and then work to promote the proper formation of noncovalent interactions that lead to the desired folded state.
[8] Chaperones begin to assist in protein folding as soon as a nascent chain longer than 60 amino acids emerges from the ribosome exit channel.
This cycling process is important during the folding of an individual polypeptide chain as it helps to avoid undesired interactions as well as to prevent the peptide from entering into kinetically trapped states.
Substrates that are unfolded, misfolded, or no longer required for cellular function can also be ubiquitin tagged for degradation by ATP dependent proteases, such as the proteasome in eukaryotes or ClpXP in prokaryotes.
This response acts locally in a cell autonomous fashion but can also extend to intercellular signaling to protect the organism from anticipated proteotoxic stress.
Upon a proteotoxic stimulus Hsp90 is recruited away from HSF, which can then bind to heat response elements in the DNA and upregulate gene expression of proteins involved in the maintenance of proteostasis.
Work on the model organism C. elegans has shown that neurons play a role in this intercellular communication of cytosolic HSR.
Stress induced in the neurons of the worm can in the long run protect other tissues such as muscle and intestinal cells from chronic proteotoxicity.
The classic examples are missense mutations and deletions that change the thermodynamic and kinetic parameters for the protein folding process.
Model systems of diverse misfolding-prone disease proteins have so far revealed numerous chaperone and co-chaperone modifiers of proteotoxicity.
Metabolic disease, such as that associated with obesity, alters the ability of cellular proteostasis networks adapt to stress, often with detrimental health effects.
[1] Over time, the proteostasis network becomes burdened with proteins modified by reactive oxygen species and metabolites that induce oxidative damage.
The IGFR-1 pathway has been shown in C. elegans to protect against these harmful aggregates, and some experimental work has suggested that upregulation of insulin growth factor receptor 1 (IGFR-1) may stabilize proteostatic network and prevent detrimental effects of aging.
[1] Vertex Pharmaceuticals and Pfizer sell regulatory agency approved pharmacologic chaperones for ameliorating cystic fibrosis and the transthyretin amyloidoses, respectively.
[23] It has been suggested that this approach could even be applied prophylactically, such as upregulating certain protective pathways before experiencing an anticipated severe cellular stress.
