Integrated stress response

[2] In a cell experiencing normal conditions, eIF2 aids in the initiation of mRNA translation and recognizing the AUG start codon.

[1] However, once eIF2α is phosphorylated, the complex’s activity reduces, causing reduction in translation initiation and protein synthesis, while promoting expression of the ATF4 gene.

The presence of heme causes a disulfide bond to form between the monomers of HRI, resulting in the structure of an inactive dimer.

[1] PKR (encoded in humans by the gene EIF2AK2) activation is mainly dependent on the presence of double-stranded RNA during a viral infection.

[1] Once activated, PKR will phosphorylate eIF2α which causes a cascade of events that result in viral and host protein synthesis being inhibited.

[1] The ATF4 transcription factor has the ability to form dimers with many different proteins that influence gene expression and cell fate.

[3] On the other hand, ATF4 and CHOP work together to induce cell death, as well as regulating amino acid biosynthesis, transport and metabolic processes.

The presence of a leucine zipper domain (bZIP) allows ATF4 to work together with many other proteins, thus creating specific responses to different types of stressors.

In addition, when a cell is undergoing amino acid starvation or endoplasmic reticulum stress, TRIP3 also interacts with ATF4 to decrease activity.

[6] These autophagosomes can carry unneeded organelles and proteins, as well as damaged or harmful components in an attempt by the cell to maintain homeostasis.

However, dephosphorylation of eIF2α can also facilitate the production of death-inducing proteins in cases where the cell is so severely damaged that normal functioning cannot be restored.

This results in cells exhibiting issues with amino acid transport, glutathione biosynthesis and oxidative stress resistance.

When a mutation inhibits the functioning of PERK, endogenous peroxides accumulate when the cell experiences endoplasmic reticulum stress.

[1] In mice and humans lacking PERK, there have been observed destruction of secretory cells undergoing high endoplasmic reticulum stress.