Unfolded Protein Response

From Anvita Health Wiki

Introduction

• reactive response evoked to provide cellular protection
• 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:

• NGLY1/SAKS1/AMFR/VCP/RAD23B complex
• UFD1L/VCP/NPLOC4
• SELS/ VIMP & SYVN1
• DERL1, DERL2 & DERL3

• 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 inhibited by guanbenz [6]

More General Terms

• biochemistry

References

1. Larner SF, Hayes RL, Wang KK. Unfolded protein response after neurotrauma. J Neurotrauma. 2006 Jun;23(6):807-29. PMID: [1]
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: [2]
3. UniProt [3]
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 [4]
6. Tsaytler P et al. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 2011 Apr 1; 332:91. PMID: [5]
7. Alavez S et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 2011 Apr 14; 472:226 PMID: [6]

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