BMED 5207 PERK and GCN2 activation, IRE1-XBP1 pathway (exam 3)

step 1 of PERK activation

ER stress (accumulation of misfolded proteins in ER lumen)

step 2 of PERK activation

the ER chaperone PiP is sequesterd by misfolded proteins in the ER lumen

step 3 of PERK activation

PERK releases BiP. The release of BiP by PERK leads to PERK dimerization and activation of its kinase domain. PERK phosphorylates itself and eIF2

step 4 of PERK activation

Phosphorylation of eIF2 causes global inhibition of translation but the translation of ATF increases

step 5 of PERK activation

ATF4 (transcription factor) induces expression of many stress repsonse proteins

GCN2 activated by

non-acylated tRNAs

when does the concentration of non-aceylated tRNAs increase in the cytosol?

during amino acid starvation

pathway of GCN2 and PERK to expressionof stress response genes

eIF2 is phosphorylated by GCN2 and PERK, which blocks general protein synthesis and leads to translation of ATF4 mRNA and the induction of expressionof many stress response genes

GADD34 dependent negative feed-back regulation of translational repression

ATF4 translation leads to upregulation of GADD34, which provides a scafforld for interaction between PP1 and P-eIF2a and eIF2a is dephosphorylated

Step 1 of IRE-XBP1 pathway

BiP is sequestered by misfolded proteins in th ER lumen

Step 2 of IRE-XBP1 pathway

IRE1 releases BiP; IRE1 dimerizes

step 3 of IRE-XBP1 pathway

auto- and cross-phosphoriylation in the IRE1 dimer, leading to activation of IRE1 endonuclease activity

step 4 of IRE-XBP1 pathway

IRE1 splices out an 26-nucleotide region from the XBP1 mRNA. This changes the reading frame of XBP1 and it changes the C-terminal half of the XBP1 protein.

step 5 of IRE-XBP1 pathway

XBP1s axtivates the transcription of genes that contain ER stress elements (ERSE) in their promoter

ERSE

ER stress elements