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unfolded protein response; misfolded protein response; proteostasis; endoplasmic reticulum associated protein degradation (UPR, ERAD)

Physiology: 1) reactive response evoked to provide cellular protection - dynamic regulation of protein homeostasis [9] 2) occurs when endoplasmic reticulum (ER) membrane-bound sensor proteins detect the excess accumulation of misfolded or unfolded proteins within the ER lumen 3) recognition of misfolded proteins occurs via detection of exposed hydrophobic regions, unpaired Cys & immature glycans 4) after recognition in the endoplasmic reticulum, polyubiquitination drives the transport of misfolded proteins into the cyoplasm for degradation by ubiquitin proteasome system 5) activation leads to a) general protein translation shut-down b) transcriptional induction c) translation of proteases & associated proteins to degrade misfolded or unfolded proteins d) induces PERK, BLIMP1 [2], IRE1, ATF6 6) if the stress is prolonged, caspase-12 & other apoptotic proteins are activated, triggering programmed cell death 7) any protein that can bind BIP (GRP-78) activates the UPR [4] 8) components of response may include: a) NGLY1/SAKS1/AMFR/VCP/RAD23B complex b) UFD1L/VCP/NPLOC4 c) SELS/VIMP & SYVN1 d) DERL1, DERL2 & DERL3 e) TOR [8] 9) protein phosphatase-1 catalyzes stress-induced dephosphorylation of eIF2-alpha & promotes stress-induced protein synthesis a) this increases the burden on chaperones in ensuring proper protein folding [6] b) when protein synthesis rates exceed the capacity of chaperones to ensure proper protein folding, the misfolded protein response occurs c) protein phosphatase-1 catalyzed dephosphorylation of eIF2-alpha is inhibited by guanbenz [6] Pathology: - loss of the unfolded protein response (proteostasis) may contribute to Alzheimer's disease, Parkinson's disease, & sarcopenia [8]

General

biochemistry

References

  1. Larner SF, Hayes RL, Wang KK. Unfolded protein response after neurotrauma. J Neurotrauma. 2006 Jun;23(6):807-29. PMID: 16774469
  2. 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: 16708403
  3. UniProt :accession P55072
  4. 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
  5. Wikipedia: Endoplasmic Reticulum Associated Protein Degradation http://en.wikipedia.org/wiki/Endoplasmic_Reticulum_Associated_Protein_Degradation
  6. Tsaytler P et al. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 2011 Apr 1; 332:91. PMID: 21385720
  7. Alavez S et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 2011 Apr 14; 472:226 PMID: 21451522
  8. Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  9. Wajngarten M Is There Hope in the Fight Against Aging? Medscape. December 19, 2022 https://www.medscape.com/viewarticle/985809