Unfolded protein response

The unfolded protein response (UPR) is a cellular stress response activated in eukaryotic cells in response to endoplasmic reticulum (ER) stress, an accumulation of unfolded proteins in the ER lumen. ER Stress can be caused by different conditions such as high protein demand, viral infection, energy deprivation or excessive oxidative stress. UPR signalling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate1. The regulation of UPR is mediated by three major proteins, namely inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK)2. The unfolded Protein Response Regulator BiP/GRP78 has the abiliity to bind and inactivate them3. Misfolded proteins bind and sequester BiP which releases the UPR effector proteins and therefore reactivate them. Activation of PERK leads to phosphorylation of eukaryotic initiation factor (eIF). Phosphorylated elf-2α inhibits protein translation in order to restore homeostasis and enables ATF4 as well. In response to ER stress, ATF6p90 transits to the Golgi where it is cleaved by site-1 protease (S1P) and site-2 protease (S2P), yielding the active transcription factor, ATF6p504. IRE1 oligomerises and activates its ribonuclease domain through auto phosphorylation. Activated IRE1 catalyses the excision of a 26 nucleotide intron from XBP1u mRNA, in a similar manner to pre-tRNA splicing5. Removal of this intron causes a frame shift in the XBP1 coding sequence resulting in the translation of a 376 amino acid, 40 kDa, XBP-1s isoform. Active ATF6p50 and XBP1 subsequently bind to the ER stress response element (ERSE) and the UPR element (UPRE), leading to expression of target genes encoding ER chaperones and ER-associated degradation (ERAD) factors involved in degradation of unfolded proteins6. The outcome of UPR activation increases protein folding, transport and ER-associated protein degradation (ERAD), while attenuating protein synthesis to restore ER homeostasis. If these adaptive mechanisms cannot resolve the protein-folding defect, cells enter apoptosis.

References:

  1. Hetz C, (2012): “The unfolded protein response: Controlling cell fate decisions under ER stress and beyond.” Mol Cell Biol.;13:89–102. [PMID: 22251901]
  2. Ron D, (2007): “Signal integration in the endoplasmic reticulum unfolded protein response.” Nat Rev Mol Cell Biol., Jul;8(7):519-29. . [PMID: 17565364]
  3. Bertolotti A, Zhang Y, (2000): "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response.” Nat Cell Biol, Jun;2(6):326-32.. [PMID: 10854322]
  4. Jin Ye (2000): “ER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases that Process SREBPs” Molecular Cell, Volume 6, Issue 6, Pages 1355-1364 [DOI: 10.1016/S1097-2765(00)00133-7]
  5. Yanagitani K (2009): “Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA.” Mol Cell, Apr 24;34(2):191-200 [PMID: 19394296]
  6. Zhang K, Kaufman RJ. (2006): “The unfolded protein response: a stress signaling pathway critical for health and disease.” Neurology, 66:S102-9 [PMID: 15363493]

Initiation Factors

Antigens in this category:
PRKCB - PKC beta: PRKCB antibodies PRKCB ELISA Kits PRKCB Proteins
XBP1 (X-Box Binding Protein 1): XBP1 antibodies XBP1 ELISA Kits XBP1 Proteins
CREBRF (CREB3 Regulatory Factor): CREBRF antibodies   CREBRF Proteins
CREB3 (CAMP Responsive Element Binding Protein 3): CREB3 antibodies CREB3 ELISA Kits CREB3 Proteins
ATF6 (Activating Transcription Factor 6): ATF6 antibodies ATF6 ELISA Kits ATF6 Proteins
ATF4 (Activating Transcription Factor 4 (Tax-Responsive Enhancer Element B67)): ATF4 antibodies ATF4 ELISA Kits ATF4 Proteins
ATF3 (Activating Transcription Factor 3): ATF3 antibodies ATF3 ELISA Kits ATF3 Proteins

Chaperones

Antigens in this category:
PDIA2 (Protein Disulfide Isomerase Family A, Member 2): PDIA2 antibodies PDIA2 ELISA Kits PDIA2 Proteins
PFDN6 - Prefoldin Subunit 6: PFDN6 antibodies PFDN6 ELISA Kits PFDN6 Proteins
PFDN5 (Prefoldin Subunit 5): PFDN5 antibodies PFDN5 ELISA Kits PFDN5 Proteins
PFDN4 - Prefoldin Subunit 4: PFDN4 antibodies PFDN4 ELISA Kits PFDN4 Proteins
PFDN3 - Prefoldin Subunit 3: PFDN3 antibodies PFDN3 ELISA Kits PFDN3 Proteins
PFDN2 - Prefoldin Subunit 2: PFDN2 antibodies PFDN2 ELISA Kits PFDN2 Proteins
PFDN1 (Prefoldin Subunit 1): PFDN1 antibodies PFDN1 ELISA Kits PFDN1 Proteins
SIL1 (SIL1 Homolog, Endoplasmic Reticulum Chaperone (S. Cerevisiae)): SIL1 antibodies SIL1 ELISA Kits SIL1 Proteins
UXT (Ubiquitously-Expressed, Prefoldin-Like Chaperone): UXT antibodies UXT ELISA Kits UXT Proteins
CALR - Calreticulin: CALR antibodies CALR ELISA Kits CALR Proteins
ATP6V0D1 (ATPase, H+ Transporting, Lysosomal 38kDa, V0 Subunit D1): ATP6V0D1 antibodies ATP6V0D1 ELISA Kits ATP6V0D1 Proteins

Regulator & Messenger

Antigens in this category:
CCL2 - Chemokine (C-C Motif) Ligand 2: CCL2 antibodies CCL2 ELISA Kits CCL2 Proteins
BAX (BCL2-Associated X Protein): BAX antibodies BAX ELISA Kits BAX Proteins
BAK1 (BCL2-Antagonist/killer 1): BAK1 antibodies BAK1 ELISA Kits BAK1 Proteins

Apoptose Induction

Antigens in this category:
TOMM20 (Translocase of Outer Mitochondrial Membrane 20 Homolog (Yeast)): TOMM20 antibodies TOMM20 ELISA Kits TOMM20 Proteins
CASP12 - Caspase 12: CASP12 antibodies CASP12 ELISA Kits  
CASP12 - Caspase 12: CASP12 antibodies CASP12 ELISA Kits  

Membran Receptor & Transporter

Antigens in this category:
TRAF2 (TNF Receptor-Associated Factor 2): TRAF2 antibodies TRAF2 ELISA Kits TRAF2 Proteins
ERN1 (Endoplasmic Reticulum To Nucleus Signaling 1): ERN1 antibodies ERN1 ELISA Kits ERN1 Proteins
SLC6A8 (Solute Carrier Family 6 (Neurotransmitter Transporter, Creatine), Member 8): SLC6A8 antibodies SLC6A8 ELISA Kits SLC6A8 Proteins
ARFGAP1 (ADP-Ribosylation Factor GTPase Activating Protein 1): ARFGAP1 antibodies ARFGAP1 ELISA Kits ARFGAP1 Proteins
PEK-1 - Human PERK Kinase Homolog Family Member (Pek-1):      

Protein Kinase

Antigens in this category:
MAP3K5 (Mitogen-Activated Protein Kinase Kinase Kinase 5): MAP3K5 antibodies MAP3K5 ELISA Kits MAP3K5 Proteins
PPP1R15A - Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 15A: PPP1R15A antibodies PPP1R15A ELISA Kits PPP1R15A Proteins
JAK3 (Tyrosine-Protein Kinase JAK3): JAK3 antibodies JAK3 ELISA Kits JAK3 Proteins
JAK1 (Janus Kinase 1): JAK1 antibodies JAK1 ELISA Kits JAK1 Proteins
JAK2 (Janus Kinase 2): JAK2 antibodies JAK2 ELISA Kits JAK2 Proteins