Endoplasmic reticulum stress response in coronavirus infection (Homo sapiens)
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Description
Activated PERK inactivates eIF2α by phosphorylation, leading to a decrease in overall protein synthesis. eIF2α can also be phosphorylated by several other kinases (HRI, GCN2, PKR). Via the preferential translation of a few genes, including ATF4 and CHOP, apoptosis is induced in cells with prolonged ER stress, and a negative feedback loop enables restart of protein synthesis once ER stress is resolved. Activated IRE1 (ERN1) has multiple downstream effects. The IRE1 RNase domain is involved in unconventional splicing of XBP1, creating XBP1S which induces expression of genes involved in protein folding. The RNase domain can also break down mRNAs (IRE1-dependent mRNA decay, RIDD), helping to establish ER homeostasis. The IRE1 kinase domain Finally, the kinase activity of IRE1 also activates a signaling cascade that ultimately activates the JNK pathway via a signaling cascade, leading to apoptosis. Activated ATF6 is translocated to Golgi and cleaved to release ATF6-p50, a transcription factor that induces the expression of protein chaperone genes as well as CHOP and XBP1. There is evidence that SARS-CoV infection inhibits ATF6 cleavage.
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