Fig. 3.

ZIKV proteins localize to the endoplasmic reticulum (ER) and cause molecular and structural changes. a) Zika virus (ZIKV) indirectly interacts with AXL receptor and internalizes into the host cells through clathrin-mediated endocytosis. 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 co-translational 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