Integrated stress response

The integrated stress response can be triggered within a cell due to either extrinsic or intrinsic conditions. Extrinsic factors include hypoxia, amino acid deprivation, glucose deprivation, viral infection and presence of oxidants. The main intrinsic factor is endoplasmic reticulum stress due to the accumulation of unfolded proteins. It has also been observed that the integrated stress response may trigger due to oncogene activation. The integrated stress response will either cause the expression of genes that fix the damage in the cell due to the stressful conditions, or it will cause a cascade of events leading to apoptosis, which occurs when the cell cannot be brought back into homeostasis. == eIF2 protein complex ==

Stress signals can cause protein kinases, known as EIF-2 kinases, to phosphorylate the α subunit of a protein complex called translation initiation factor 2 (eIF2), resulting in the gene ATF4 being turned on, which will further affect gene expression. In a cell experiencing normal conditions, eIF2 aids in the initiation of mRNA translation and recognizing the AUG start codon. 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. == Protein kinases ==

There are four known mammalian protein kinases that phosphorylate eIF2α, including PKR-like ER kinase (PERK, EIF2AK3), heme-regulated eIF2α kinase (HRI, EIF2AK1), general control non-depressible 2 (GCN2, EIF2AK4) and double stranded RNA dependent protein kinase (PKR, EIF2AK2). PERK PERK (encoded in humans by the gene EIF2AK3) responds mainly to endoplasmic reticulum stress and has two modes of activation. The pathways for this activation require further research, although multiple models have been proposed, including crosslinking between GCN2 and tRNA. PKR PKR (encoded in humans by the gene EIF2AK2) activation is mainly dependent on the presence of double-stranded RNA during a viral infection. dsRNA causes PKR to form dimers, resulting in autophosphorylation and activation. Once activated, PKR will phosphorylate eIF2α which causes a cascade of events that result in viral and host protein synthesis being inhibited. Other stressors that cause the activation of PKR include oxidative stress, endoplasmic reticulum stress, growth factor deprivation and bacterial infection. Caspase activity early on in apoptosis has also been observed to trigger activation of PKR. However, these stressors differ in that they activate PKR without using dsRNA. == ATF4 ==

When a cell is subjected to stressful conditions, the ATF4 gene is expressed. During this process, the cell forms autophagosomes, or double membraned vesicles, that allow for transportation of material throughout the cell. These autophagosomes can carry unneeded organelles and proteins, as well as damaged or harmful components in an attempt by the cell to maintain homeostasis. == Termination of integrated stress response ==

In order to terminate the integrated stress response, dephosphorylation of eIF2α is required. The protein phosphatase 1 complex (PP1) aids in the dephosphorylation of eIF2α. This complex contains a PP1 catalytic subunit as well as two regulatory subunits. This complex is negatively regulated by two proteins: growth arrest and DNA damage‐inducible protein (GADD34), also known as PPP1R15A, or constitutive repressor of eIF2α phosphorylation (CReP), also known as PPP1R15B. CReP acts to keep levels of eIF2α phosphorylation low in cells under normal conditions. GADD34 is produced in response to ATF4 and works to increase dephosphorylation of eIF2α. The dephosphorylation of eIF2α results in the return of normal protein synthesis and cellular function. 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. == Mutations affecting integrated stress response ==

Mutations that affect the functioning of the integrated stress response may have debilitating effects on cells. For example, cells lacking the ATF4 gene are unable to elicit proper gene expression in response to stressors. 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. In mice and humans lacking PERK, there have been observed destruction of secretory cells undergoing high endoplasmic reticulum stress. == See also ==