Author: Mohd Ropidi, Muhammad Izzuddin; Khazali, Ahmad Suhail; Nor Rashid, Nurshamimi; Yusof, Rohana
Title: Endoplasmic reticulum: a focal point of Zika virus infection Document date: 2020_1_20
ID: 0zr2e8lh_35
Snippet: Similar to IRE1, release of GRP78 proteins enable misfolded/unfolded proteins binding onto exposed PERK luminal domain leading to oligomerization and autophosphorylation of PERK protein to activate its downstream pathway [55, 68] . PERK phosphorylation, in turn, induces eIF2α phosphorylation (p-eIF2α) that mediates three interlinked UPR mechanisms: expansion of protein folding capacity, suppression of nascent protein production and induction of.....
Document: Similar to IRE1, release of GRP78 proteins enable misfolded/unfolded proteins binding onto exposed PERK luminal domain leading to oligomerization and autophosphorylation of PERK protein to activate its downstream pathway [55, 68] . PERK phosphorylation, in turn, induces eIF2α phosphorylation (p-eIF2α) that mediates three interlinked UPR mechanisms: expansion of protein folding capacity, suppression of nascent protein production and induction of apoptosis in the event of severe stress [69] . Phosphorylation of α subunit in the eIF2 complex hinders the assembly of preinitiation complex (PIC) by blocking the activity of eIF2B guanine exchange factor, leading to global suppression of mRNA translation [69] . However, selected mRNAs, typically transcripts for UPR machinery, can bypass this translational block [69] . Interestingly, viruses have evolved various mechanisms to overcome this translational block, but the mechanism of this process in ZIKV infection is unclear. Recent analyses of ZIKV infection in vitro and in vivo reported a substantial increase of eIF2α phosphorylation and elevated expression of several downstream PERK effectors such as ATF4, ATF3, CHAC1, and CHOP [48, 49] . Importantly, intracerebroventricular administration of pharmacological PERK inhibitor in ZIKV-infected mice restored appropriate neurogenesis balance and rescued infected mouse embryos from microcephalic phenotype. However, unlike IRE1 inhibitor, PERK inhibitor did not affect ZIKV replication [49] . PERK inhibitor also prevented microcephaly in placental ZIKV inoculation model, which mimics natural ZIKV vertical transmission [49] .
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