unfolded protein response; misfolded protein response; proteostasis; endoplasmic reticulum associated protein degradation (UPR, ERAD)
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Pathology
- loss of the unfolded protein response (proteostasis) may contribute to Alzheimer's disease, Parkinson's disease, & sarcopenia[8]
Physiology
- reactive response evoked to provide cellular protection
- dynamic regulation of protein homeostasis[9]
- occurs when endoplasmic reticulum (ER) membrane-bound sensor proteins detect the excess accumulation of misfolded or unfolded proteins within the ER lumen
- recognition of misfolded proteins occurs via detection of exposed hydrophobic regions, unpaired Cys & immature glycans
- after recognition in the endoplasmic reticulum, polyubiquitination drives the transport of misfolded proteins into the cyoplasm for degradation by ubiquitin proteasome system
- activation leads to
- general protein translation shut-down
- transcriptional induction
- translation of proteases & associated proteins to degrade misfolded or unfolded proteins
- induces PERK, BLIMP1[2], IRE1, ATF6
- if the stress is prolonged, caspase-12 & other apoptotic proteins are activated, triggering programmed cell death
- any protein that can bind BIP (GRP-78) activates the UPR[4]
- components of response may include:
- protein phosphatase-1 catalyzes stress-induced dephosphorylation of eIF2-alpha & promotes stress-induced protein synthesis
- this increases the burden on chaperones in ensuring proper protein folding[6]
- when protein synthesis rates exceed the capacity of chaperones to ensure proper protein folding, the misfolded protein response occurs
- protein phosphatase-1 catalyzed dephosphorylation of eIF2-alpha is inhibited by guanbenz[6]
More general terms
References
- ↑ Larner SF, Hayes RL, Wang KK. Unfolded protein response after neurotrauma. J Neurotrauma. 2006 Jun;23(6):807-29. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16774469
- ↑ 2.0 2.1 Doody GM, Stephenson S, Tooze RM. BLIMP-1 is a target of cellular stress and downstream of the unfolded protein response. Eur J Immunol. 2006 Jun;36(6):1572-82. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16708403
- ↑ UniProt http://www.uniprot.org/uniprot/P55072.html
- ↑ 4.0 4.1 Kaufman R, University of Michigan Proceedings of the 38th Annual Meeting of the American Aging Association: Integrative Biology: Hormones, Signaling, and Aging. May 29-June 1, 2009, Scottsdale, AZ
- ↑ Wikipedia: Endoplasmic Reticulum Associated Protein Degradation http://en.wikipedia.org/wiki/Endoplasmic_Reticulum_Associated_Protein_Degradation
- ↑ 6.0 6.1 6.2 Tsaytler P et al. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 2011 Apr 1; 332:91. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21385720
- ↑ Alavez S et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 2011 Apr 14; 472:226 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21451522
- ↑ 8.0 8.1 8.2 Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
- ↑ 9.0 9.1 Wajngarten M Is There Hope in the Fight Against Aging? Medscape. December 19, 2022 https://www.medscape.com/viewarticle/985809