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5’cap

eIF2 a kinase. 40S. a. tRNA Met. tRNA Met. tRNA Met. tRNA Met. tRNA Met. b. 40S. g. PO 3. 40S. 40S. 40S. 40S. GTP. GTP. GDP. GTP. GTP. GTP. GTP. 60S. 60S. Translation initiation factor eIF2: Initiation and Recycling.

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5’cap

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  1. eIF2a kinase 40S a tRNAMet tRNAMet tRNAMet tRNAMet tRNAMet b 40S g PO3 40S 40S 40S 40S GTP GTP GDP GTP GTP GTP GTP 60S 60S Translation initiation factor eIF2: Initiation and Recycling Phosphorylation of eIF2a reduces the concentration of the eIF2-GTP-tRNAMet eIF2-GTP-tRNAMet Ternary Complex eIF2 eIF2B 5’cap AUG

  2. 40S 40S 40S 40S 40S 40S 40S 40S 40S 40S 40S 40S GTP GTP GTP GTP GTP GTP GDP GDP GTP GTP GDP GDP 40S 40S 40S 40S 40S uORF 60S 60S 60S 60S 60S 60S 60S Selection of alternative in-frame start codons are sensitive to eIF2 alpha phosphorylation AUG AUG High concentration of eIF2-GTP-tRNAMet Repressed translation uORF uORF GCN4 Low concentration of eIF2-GTP-tRNAMet Derepressed translation uORF GCN4

  3. PERK GCN2 HRI PKR eIF2a kinases Amino acid deprivation (binding uncharged tRNAs) Calcium mobilization or misfolded proteins (disassociation of BiP-GRP78) Heme deprivation (disassociation of hemin) Viral infection (binding dsRNA) PO3 NRF-2 a g eIF2 b Transcription ( - ) ( + ) Initiation of protein synthesis mRNA specific translation initiation

  4. Thapsigargin Inactive PERK Activated PERK Repression of global protein synthesis Adaptation to stress or apoptosis (e.g. activation ATF-4 -> CHOP) Activation of PERK via ER stress and loss of ER calcium Endoplasmic reticulum Ca2+ = 5x10-5M RyR SERCA BiP Ca2+ IP3R ATP

  5. Ligand Inactive PERK Activated PERK Receptor-mediated generation of IP3 and/or activation of voltage-gated channels stimulates ER calcium mobilization and activation of PERK Ca2+ GCPR Endoplasmic reticulum IP3 Ca2+ = 5x10-5M IP3R SERCA BiP Ca2+ RyR Ca2+ ATP

  6. Glucose metabolism increases ER calcium and represses PERK glucose exocytosis . . . VGCC K+ATP GLUT2 PMCA plasma membrane Ca2+ Ca2+ (10-7M) K+ . . . . . . Ca2+ . . ATP Secreted proteins Secretory machinery Differentiation factors Proliferatiaon factors IP3R SERCA ER nucleus Ca2+ (5x10-5M) BiP Transcription factors Translation control of specific mRNAs Activated dimerized PERK Inactive PERK

  7. 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 ATP ATP Ca2+ Ca2+ ATP Inactive PERK Activated PERK Ca2+ Glucose Endoplasmic reticulum Ca2+ RyR SERCA BiP Ca2+ RYR

  8. Extracellular physiological, developmental, and stress signals Intracellular signals Protein synthesis ER signals Translation of specific genes Reduction of co-translational import Modulation of secretory capacity: maintenance of differentiated state, cell mass, secretory machinery PERK sensor ER nucleus

  9. 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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