Key Points
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Protein homeostasis (also known as proteostasis) is an integrated system comprising folding chaperones and factors, degradation components and compartmentalized folding environments that generate, protect and degrade the protein fold. These activities preserve biological function and can enable the fold to dynamically change in response to the local environment.
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In all organisms — Bacteria, Archaea and Eukarya— proteostasis has co-evolved with the proteome to maintain the health of the cell and to respond to the unique stresses that different cells or organisms experience.
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The components of the proteostasis network of any given organism are optimized for its niche, which is exemplified by the heat shock protein (HSP) family of chaperones.
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Multiple lessons have been learnt from surveying proteostasis networks from different organisms, and the need for increasing the complexity of proteostasis management systems with increasing size of the genome and gene expression patterns is becoming clear.
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Evidence suggests that the proteostasis network and the proteome have co-evolved to promote organismal survival in different niches. The proteostasis network is a driver of evolvability, facilitating both adaptation and natural selection by closely managing the link between the phenotype and the genotype to insure both short-term cell survival and to bring long-term benefits by fixing new traits into the genome, leading to enhanced fitness.
Abstract
Although the sequence of a protein largely determines its function, proteins can adopt different folding states in response to changes in the environment, some of which may be deleterious to the organism. All organisms —Bacteria, Archaea and Eukarya — have evolved a protein homeostasis, or proteostasis, network comprising chaperones and folding factors, degradation components, signalling pathways and specialized compartmentalized modules that manage protein folding in response to environmental stimuli and variation. Surveying the origins of proteostasis networks reveals that they have co-evolved with the proteome to regulate the physiological state of the cell, reflecting the unique stresses that different cells or organisms experience, and that they have a key role in driving evolution by closely managing the link between the phenotype and the genotype.
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Acknowledgements
The authors gratefully acknowledge their colleagues J. W. Kelly, R. Morimoto and A. Dillin for helpful discussions. E.T.P. was supported by grants from the US National Institutes of Health (NIH) (AG03109); W.E.B. was supported by grants from the NIH (GM42236, GM33301, AG03109, HL079442, HL095524) and the Cystic Fibrosis Foundation.
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William E. Balch is a consultant at Proteostasis Therapeutics, Cambridge, Massachusetts, USA. Evan T. Powers declares no competing financial interests.
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Glossary
- Membrane trafficking compartments
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Subcellular organelles enriched in proteostasis network components, some of which have cytoplasmic homologues and some of which are unique to each compartment, that fold and transport transmembrane and extracellular cargo proteins. Generation and movement between compartments is managed by integrated coat, tether and fusion components.
- Healthspan
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The period during which an organism, particularly a human, is healthy and free of diseases that compromise longevity.
- Evolvability
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The capacity of a biological system to evolve and adapt to the environment. Adaptive evolution is the process in which beneficial mutations are fixed in the genome through positive selection.
- Cages
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The space within the oligomeric, ring-like structures of heat shock protein 60 (HSP60)-type chaperones in which proteins can fold isolated from the other components of the cytosol. Often referred to as an Anfinsen cage.
- Last universal common ancestor
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(LUCA). The organism from which all extanst organisms on earth descend. It is estimated to have lived 3.5 to 3.8 billion years ago.
- SOS response
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A stress response that is triggered by DNA damage. It induces the expression of proteins involved in DNA repair.
- Horizontal gene transfer
-
The transfer of genes between organisms in a manner other than traditional reproduction. This can occur through transformation (uptake and expression of foreign genetic material), transduction (movement of genetic material by viruses), bacterial conjugation (cell-to-cell contact resulting in the delivery of genetic material) and gene transfer agents that include virus-like elements that are encoded by the host.
- P-transposable element
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A genetic element that can jump to different sites in a genome. This type of transposable element is present specifically in Drosophila melanogaster.
- Cryptic phenotypes
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An inactive, masked or hidden activity state that becomes functional in response to folding stress.
- Nucleosome
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The basic unit of DNA packaging in the chromatin structure of Eukarya, consisting of a segment of DNA wound around histone protein cores. Nucleosome compactness and hence the access for transcription factors are subject to the epigenetic activity of acetylation and deacetylation by histone acetylases and histone deacetylases, respectively.
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Powers, E., Balch, W. Diversity in the origins of proteostasis networks — a driver for protein function in evolution. Nat Rev Mol Cell Biol 14, 237–248 (2013). https://doi.org/10.1038/nrm3542
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DOI: https://doi.org/10.1038/nrm3542
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