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Translation initiation factor eIF2: Initiation and Recycling
Phosphorylation of eIF2a reduces the concentration of the eIF2-GTP-tRNAMet eIF2-GTP-tRNAMet Ternary Complex eIF2 a b g GTP 40S GTP tRNAMet eIF2B 40S tRNAMet GTP eIF2a kinase PO3 GDP tRNAMet 40S GTP tRNAMet 40S GTP tRNAMet 40S GTP 60S 40S 5’cap AUG 60S
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Repressed translation GCN4 Derepressed translation GCN4
High concentration of eIF2-GTP-tRNAMet GDP GTP GDP Repressed translation 40S 40S GTP 40S GTP 40S GTP 40S uORF uORF GCN4 60S 60S 60S 60S Low concentration of eIF2-GTP-tRNAMet Derepressed translation GDP GTP GDP 40S GTP 40S GTP 40S GTP 40S 40S 40S uORF uORF GCN4 60S 60S 60S AUG Selection of alternative in-frame start codons are sensitive to eIF2 alpha phosphorylation
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PO3 a g eIF2 b eIF2a kinases GCN2 HRI PERK PKR ( - ) ( + ) NRF-2
Amino acid deprivation (binding uncharged tRNAs) Calcium mobilization or misfolded proteins (disassociation of BiP-GRP78) Heme deprivation (disassociation of hemin) GCN2 HRI PERK Viral infection (binding dsRNA) PKR PO3 NRF-2 a g b eIF2 Transcription ( - ) ( + ) Initiation of protein synthesis mRNA specific translation initiation
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Activation of PERK via ER stress and loss of ER calcium
Endoplasmic reticulum Thapsigargin Ca2+ = 5x10-5M SERCA RyR BiP Ca2+ IP3R Activated PERK Inactive PERK ATP Repression of global protein synthesis Adaptation to stress or apoptosis (e.g. activation ATF-4 -> CHOP)
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Receptor-mediated generation of IP3 and/or activation of voltage-gated channels stimulates ER calcium mobilization and activation of PERK Ligand Ca2+ GCPR Endoplasmic reticulum IP3 Ca2+ = 5x10-5M SERCA IP3R BiP Ca2+ RyR Activated PERK Inactive PERK Ca2+ ATP
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. Glucose metabolism increases ER calcium and represses PERK Ca2+
IP3R VGCC exocytosis SERCA BiP PMCA plasma membrane Inactive PERK Activated dimerized PERK Translation control of specific mRNAs ER nucleus Secreted proteins Secretory machinery Differentiation factors Proliferatiaon factors Transcription factors Ca2+ (10-7M) Ca2+ (5x10-5M) K+ATP GLUT2 glucose ATP K+ Glucose metabolism increases ER calcium and represses PERK
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Glucose metabolism generating ATP and driving sustainted
Calcium uptake in the ER by the SERCA calcium pump ATPase Glucose metabolism driving transient calcium-induced calcium release from the ER Glucose Ca2+ ATP ATP Endoplasmic reticulum Ca2+ Ca2+ SERCA RyR BiP Ca2+ RYR Activated PERK Inactive PERK
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PERK sensor Reduction of co-translational import ER
Extracellular physiological, developmental, and stress signals Intracellular signals ER signals PERK sensor Protein synthesis Reduction of co-translational import ER Modulation of secretory capacity: maintenance of differentiated state, cell mass, secretory machinery Translation of specific genes nucleus
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PERK regulates a continuum of normal developmental and
ER stress related processes Normal developmental and physiological modulation of ER activity regulates PERK activity which in turn activates/represses genes that modulate normal growth and development. ER stress hyperactivates PERK leading to the activation of stress response genes. Thus, the degree to which PERK is activated determines which particular subset of regulatory circuits are activated or repressed.
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