Endoplasmic reticulum: a focal point of Zika virus infection

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

ATF6 is a type II ER transmembrane protein that contains a transcription activation domain (TAD) on its cytosolic-facing N-terminal and two independent Golgilocalization signals (GLS) on its luminal-facing Cterminal [51] . Following the dissociation of GRP78 that unmasks the GLS, ATF6 translocate to the Golgi apparatus and undergoes sequential proteolytic processing by Fig. 2 ZIKV-induced ER stress initiates host cell unfolded protein response (UPR). ZIKV infection induces ER stress due to the increased amount of unfolded/misfolded viral (red strand) and host cell (grey strand) protein aggregates in the ER lumen. The accumulation of these partially processed proteins leads to the overwhelming demand of correct protein folding. To facilitate protein folding, GRP78 (orange) dissociates from the stress sensors (IRE1, ATF6, and PERK) and binds to the misfolded/unfolded proteins. Expression of other chaperones is also elevated to address the overwhelming protein folding demand during ZIKV infection. Binding of misfolded protein to PERK (green) activates the sensor and triggers phosphorylation of eIF2 that in turn stimulates 1) global translational block except for selective mRNA involved in UPR, and 2) formation of stress granules. However, ZIKV bypasses global translation block and inhibits stress granules formation, but the mechanistic details of these viral interference are still unclear. Activation of ATF6 (yellow) promotes the protein proteolytical processing in the Golgi apparatus into ATF6n, ATF6n nuclear translocation, and expression of UPR target genes including XBP1. Activated IRE1 (purple) splices XBP1 transcript which produces an active transcription factor (XBP1s) that stimulates expansion of the ER volume, and expression of CHOP and ERAD factors such as EDEM-1. Alternatively, IRE1 can trigger ASK1-p38 MAPK pathway that enhances CHOP apoptotic activities and promotes other apoptotic-related activities under severe ER stress condition. Blue pointed arrows denote activation, blue blunt-end arrows denote inhibition, and red pointed arrows denote increased expression/activity site-1 and site-2 proteases, liberating TAD-containing ATF6 N-terminal (ATF6n) [51] . Subsequently, ATF6n enters the nucleus and binds to ER stress response elements in the promoter region of UPR-target genes, including X-box binding protein 1 (XBP1) transcription factor, a downstream effector of IRE1 stress sensor pathway, and GRP78 to autoregulate the UPR [51] [52] [53] .