Endoplasmic reticulum: a focal point of Zika virus infection

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

Following ZIKV infection, the accumulation of misfolded virus polyproteins in the ER lumen overwhelms the ER protein-folding capacity leading to ER stress and triggers the activation of the UPR (Fig. 2) [47] . Additional evidence of ER stress and UPR activation are demonstrated in the elevated expression of GRP78 and other chaperones such as calnexin, calreticulin, and protein disulfide isomerase (PDI) in ZIKV-infected neural cells in vitro and in vivo [35, 48, 49] . Increased expression of these ER stress markers was accompanied by impaired indirect neurogenesis and microcephalic phenotype in mice [49] . This finding is consistent with a previous report wherein the induction of UPR in cerebral apical progenitor cells tipped neuronal differentiation towards direct neurogenesis at the expense of indirect neurogenesis, leading to depleted intermediate progenitors, reduced overall cortical neuron output, and diminished cerebral volume, which ultimately caused microcephaly in vivo [50] .