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

此分类里的别的抗原:
PRKCB - PKC beta: PRKCB 抗体 PRKCB ELISA试剂盒 PRKCB 蛋白
XBP1 (X-Box Binding Protein 1): XBP1 抗体 XBP1 ELISA试剂盒 XBP1 蛋白
CREBRF (CREB3 Regulatory Factor): CREBRF 抗体   CREBRF 蛋白
CREB3 (CAMP Responsive Element Binding Protein 3): CREB3 抗体 CREB3 ELISA试剂盒 CREB3 蛋白
ATF6 (Activating Transcription Factor 6): ATF6 抗体 ATF6 ELISA试剂盒 ATF6 蛋白
ATF4 (Activating Transcription Factor 4 (Tax-Responsive Enhancer Element B67)): ATF4 抗体 ATF4 ELISA试剂盒 ATF4 蛋白
ATF3 (Activating Transcription Factor 3): ATF3 抗体 ATF3 ELISA试剂盒 ATF3 蛋白

Chaperones

此分类里的别的抗原:
PDIA2 (Protein Disulfide Isomerase Family A, Member 2): PDIA2 抗体 PDIA2 ELISA试剂盒 PDIA2 蛋白
PFDN6 - Prefoldin Subunit 6: PFDN6 抗体 PFDN6 ELISA试剂盒 PFDN6 蛋白
PFDN5 (Prefoldin Subunit 5): PFDN5 抗体 PFDN5 ELISA试剂盒 PFDN5 蛋白
PFDN4 - Prefoldin Subunit 4: PFDN4 抗体 PFDN4 ELISA试剂盒 PFDN4 蛋白
PFDN3 - Prefoldin Subunit 3: PFDN3 抗体 PFDN3 ELISA试剂盒 PFDN3 蛋白
PFDN2 - Prefoldin Subunit 2: PFDN2 抗体 PFDN2 ELISA试剂盒 PFDN2 蛋白
PFDN1 (Prefoldin Subunit 1): PFDN1 抗体 PFDN1 ELISA试剂盒 PFDN1 蛋白
SIL1 (SIL1 Homolog, Endoplasmic Reticulum Chaperone (S. Cerevisiae)): SIL1 抗体 SIL1 ELISA试剂盒 SIL1 蛋白
UXT (Ubiquitously-Expressed, Prefoldin-Like Chaperone): UXT 抗体 UXT ELISA试剂盒 UXT 蛋白
CALR - Calreticulin: CALR 抗体 CALR ELISA试剂盒 CALR 蛋白
ATP6V0D1 (ATPase, H+ Transporting, Lysosomal 38kDa, V0 Subunit D1): ATP6V0D1 抗体 ATP6V0D1 ELISA试剂盒 ATP6V0D1 蛋白

Regulator & Messenger

此分类里的别的抗原:
CCL2 - Chemokine (C-C Motif) Ligand 2: CCL2 抗体 CCL2 ELISA试剂盒 CCL2 蛋白
BAX (BCL2-Associated X Protein): BAX 抗体 BAX ELISA试剂盒 BAX 蛋白
BAK1 (BCL2-Antagonist/killer 1): BAK1 抗体 BAK1 ELISA试剂盒 BAK1 蛋白

Apoptose Induction

此分类里的别的抗原:
TOMM20 (Translocase of Outer Mitochondrial Membrane 20 Homolog (Yeast)): TOMM20 抗体 TOMM20 ELISA试剂盒 TOMM20 蛋白
CASP12 - Caspase 12: CASP12 抗体 CASP12 ELISA试剂盒  
CASP12 - Caspase 12: CASP12 抗体 CASP12 ELISA试剂盒  

Membran Receptor & Transporter

此分类里的别的抗原:
TRAF2 (TNF Receptor-Associated Factor 2): TRAF2 抗体 TRAF2 ELISA试剂盒 TRAF2 蛋白
ERN1 (Endoplasmic Reticulum To Nucleus Signaling 1): ERN1 抗体 ERN1 ELISA试剂盒 ERN1 蛋白
SLC6A8 (Solute Carrier Family 6 (Neurotransmitter Transporter, Creatine), Member 8): SLC6A8 抗体 SLC6A8 ELISA试剂盒 SLC6A8 蛋白
ARFGAP1 (ADP-Ribosylation Factor GTPase Activating Protein 1): ARFGAP1 抗体 ARFGAP1 ELISA试剂盒 ARFGAP1 蛋白
PEK-1 - Human PERK Kinase Homolog Family Member (Pek-1):      

Protein Kinase

此分类里的别的抗原:
MAP3K5 (Mitogen-Activated Protein Kinase Kinase Kinase 5): MAP3K5 抗体 MAP3K5 ELISA试剂盒 MAP3K5 蛋白
PPP1R15A - Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 15A: PPP1R15A 抗体 PPP1R15A ELISA试剂盒 PPP1R15A 蛋白
JAK3 (Tyrosine-Protein Kinase JAK3): JAK3 抗体 JAK3 ELISA试剂盒 JAK3 蛋白
JAK1 (Janus Kinase 1): JAK1 抗体 JAK1 ELISA试剂盒 JAK1 蛋白
JAK2 (Janus Kinase 2): JAK2 抗体 JAK2 ELISA试剂盒 JAK2 蛋白