Endoplasmic reticulum: a focal point of Zika virus infection

Mohd Ropidi, Muhammad Izzuddin; Khazali, Ahmad Suhail; Nor Rashid, Nurshamimi; Yusof, Rohana

IRE1 is a single-pass transmembrane protein. The protein's ER luminal domain serves as a stress sensor, whereas the cytosolic domain is sub-divided into kinase and ribonuclease (RNase) domains. Under ER stress, GRP78 releases from IRE1 luminal domain and binds onto the misfolded/unfolded proteins. This dissociative event frees the luminal domain and in turn, permits binding of the misfolded/unfolded protein onto the liberated domain [54, 55] . Consequently, IRE1 oligomerizes at its luminal domain, which brings the kinase domains in close proximity leading to auto-phosphorylation of the kinase domains [56] . The phosphorylation event at the activation loop is postulated to induce conformational changes of the RNase domain that permit a more efficient binding of RNA substrates [57] . Activated IRE1 cleaves off 26 nucleotides from XBP1 transcripts, resulting in a translational frameshift to produce a potent transcriptional activator (XBP1s) that elevates the expression of UPR-target genes to promote protein folding, processing, and secretion [53, 58] . XBP1s also modulates the expression of factors involved in ER-associated protein degradation (ERAD), a cellular process of eliminating aberrant proteins through retro-translocation and proteasomal degradation [45] .