Endoplasmic reticulum: a focal point of Zika virus infection

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

Viruses have adopted several mechanisms to repress the assembly of stress granules and utilize SG protein components for viral polyprotein synthesis instead [74] . For example, herpes simplex virus genome encodes γ 1 34.5 protein that functionally mimics the activity of GADD34 and directs the dephosphorylation of eIF2α [75] . Alternatively, coronaviruses repress the assembly of stress granules by asserting an inhibitory effect on PKR activation and upregulating the expression of GADD34 [76] . Likewise, ZIKV also suppresses the formation of stress granules in favor of virus replication by upregulating the expression of GADD34 [77] . Consistent with this finding, pharmacological inhibition of GADD34-mediated eIF2α dephosphorylation rescued SGs assembly and decreased ZIKV particles production [77] . Additionally, another study reported that ZIKV proteins, namely capsid, NS3, NS2B-NS3, and NS4A proteins, suppressed SGs assembly; however, this modulation was observed in an eIF2α-independent manner [78] . ZIKV capsid inhibited SGs assembly by forming stable complexes with SG core proteins, Ras GTPase-activating proteinbinding protein 1 (G3BP1) and caprin-1, but not with T-cell-restricted intracellular antigen 1 related (TIAR) protein [78] . ZIKV utilized these SG core proteins for viral protein and virion production. Beside regulating eIF2α phosphorylation and hijacking key SG proteins, RNA viruses were reportedly capable of interfering SGs assembly through cleaving and redistributing SGs nucleating factors [74] . It was previously reported that ZIKV NS2B-NS3 protease could cleave host antiviral factors to impair intrinsic host defense; intriguingly, ZIKV did not mediate the cleavage of SG factors even though SGs assembly was affected by ZIKV NS3 and NS2B-NS3 protease [77] [78] [79] [80] [81] . Nonetheless, ZIKV infection was found to facilitate the redistribution of TIAR to viral replication sites, which correlates to viral replication output [77, 78, 81] . Hence, it is unclear how ZIKV NS3, NS2B-NS3, and NS4A proteins block SGs formation and whether these viral proteins affect eIF2α phosphorylation. Interestingly, a recent study also identified a key SG-interacting protein, human antigen R, exhibits substantial anti-ZIKV effect potentially by destabilizing the ZIKV RNA [81] .