Proteostasis

Proteostasis is a portmanteau of the words protein and homeostasis, and refers to the concept that there are competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking and turnover of proteins present within and outside the cell[1][2]. The concept of proteostasis maintenance is central to understanding the cause of diseases associated with excessive misfolding and degradation leading to loss-of-function phenotypes,[3] as well as aggregation-associated degenerative disorders.[4] Therefore, adapting proteostasis should enable the restoration of proteostasis, once its loss leads to pathology.

Cellular proteostasis is key to ensuring successful development, healthy aging, resistance to environmental stresses, and to minimize homeostasis perturbations by pathogens such as viruses. Proteostasis in distinct subcellular environments is constantly monitored by stress-responsive signaling pathways[5] unique to those compartments, which match proteostasis capacity to demand employing a transcriptional program and translational attenuation. Transcriptional up- and down-regulation enhances folding and degradation capacity in unison, which is probably critical for maintaining constant protein concentrations required for normal cellular physiology. As such, maintenance of proteostasis prevents disease onset.

The proteostasis network refers to the 2000+ genes in mammals that work together as a system to control protein concentration, conformation through interactions of the proteome with chaperone systems and folding enzymes[6], protein degradation mediated by the ubiquitin proteasome system and the lysosome, subcellular location, and other attributes of the proteome.[7].

Numerous academic [8][9][10] and a few commercial organizations are currently exploring the hypothesis that the proteostasis network can be adapted with small molecules and biologics to alleviate loss-of-function diseases (e.g. lysosomal storage diseases or cystic fibrosis) and gain-of-toxic function maladies where the aggregation of proteins leads to post-mitotic tissue degeneration (e.g. Alzheimers disease) [11]

See also

References

  1. ^ Powers, E.T.; Morimoto, R.I.; Dillin, A.; Kelly, J.W.; Balch, W.E. “Biological and Chemical Approaches to Diseases of Proteostasis Deficiency” Ann. Rev. Biochem. 2009 78, 959-91.[
  2. ^ Balch WE, Morimoto RI, Dillin A, Kelly JW (Feb 2008). "Adapting proteostasis for disease intervention". Science 319: 916–919. doi:10.1126/science.1141448. PMID 18276881. 
  3. ^ Mu, T-W.; Ong, D.S.T.; Wang, Y-J; Balch, W. E.; Yates, J.R.; Segatori, L.; Kelly, J.W. .”Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases” Cell 2008 134, 769-781
  4. ^ Cohen, E., Paulsson, J. F., Blinder, P., Burstyn-Cohen, T., Du, D., Estepa, G., Adame, A., Pham, H. M., Holzenberger, M., Kelly, J. W., Masliah, E. & Dillin, A. (2009). Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157-69.
  5. ^ Ron D, Walter P. 2007. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev Mol Cell Biol 8: 519-529.
  6. ^ Hartl, F.U., Bracher, A., and Hayer-Hartl, M. (2011), and protein degradation by the ubiquitin proteasome system and the lysosome.<Molecular chaperones in protein folding and proteostasis. Nature 475, 324-332.
  7. ^ Balch WE, Morimoto RI, Dillin A, Kelly JW (Feb 2008). "Adapting proteostasis for disease intervention". Science 319: 916–919. doi:10.1126/science.1141448. PMID 18276881. 
  8. ^ Tsaytler P, Harding HP, Ron D, Bertolotti A. 2011. Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis. Science (Washington, DC, U S) 332: 91-94.
  9. ^ Enhancement of proteasome activity by a small-molecule inhibitor of USP14" B.H. Lee, M.J. Lee, S. Park, D.C. Oh, S. Elsasser, P.C. Chen, C. Gartner, N. Dimova, J. Hanna, S.P. Gygi, S.M. Wilson, R.W. King, D. Finley Nature 2010, 467:179-84.
  10. ^ Mu, T-W.; Ong, D.S.T.; Wang, Y-J; Balch, W. E.; Yates, J.R.; Segatori, L.; Kelly, J.W. .”Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases” Cell 2008 134, 769-781
  11. ^ Lindquist, S.L.; Kelly, J.W. “Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases–Progress and Prognosis” Cold Spring Harbor Perspect. Biol. doi10.1101 / cshperspect.a004507 2011, 307-340.

Useful links

Proteostasis: where do you work on the network? - Introduction to Proteostasis by Enzo Life Sciences