Endoplasmic reticulum: a focal point of Zika virus infection

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

Although the number of ZIKV cases have subsided, ZIKV remains a significant threat due to the sporadic and unpredictable nature of its outbreak. In addition, ZIKV shares the same vectors with another widespread flavivirus, DENV [93] , which is projected to increase exponentially in the future [94] . Thus, the potential re-occurrence of outbreaks, coupled with devastating neurological complications, warrants for extensive research to completely understand the virus pathophysiology for antiviral drug development. This is effectively demonstrated by several studies included in this review that employ multiple omics technologies to identify and target ER-associated ZIKV dependency factors and ER stress sensors. This strategy could pave the way in developing anti-ZIKV drugs. Other cell receptors such as DC-SIGN can also serve as ZIKV entry receptor. b) Acidic endosomal microenvironment facilitates endosomal fusion thereby, releasing ZIKV RNA genome that is immediately bound onto cytosolic ribosomes. c) Translation of the viral polyprotein (orange) likely initiates in the cytosol and continues with cotranslational insertion into the ER membrane via Sec61 translocon complex (blue). Post-translational processed ZIKV proteins induce ER structural alterations such as d) enlargement of the ER, and e) formation of convoluted membrane (CM), vesicle packets (VPs), zippered ER (zER) and viroplasms. Simultaneously, accumulation of misfolded and unfolded ZIKV proteins in the ER lumen results in f) the induction of ER stress and thus, initiates the host unfolded protein response (UPR) and other intrinsic defense mechanisms including reticulophagy and stress granule formation. ZIKV proteins g) impede formation of stress granules and h) inhibit reticulophagy to sustain viral replication. ZIKV infection also induces i) ER-derived cytoplasmic vacuolization, a visual characteristic of paraptosis. Blue pointed arrows denote activation, blue blunt-end arrows denote inhibition. Ve, virus-induced vesicle; Vi, virus particle