Ribosomal stress and Tp53-mediated neuronal apoptosis in response to capsid protein of the Zika virus

Abstract

We report here that in rat and human neuroprogenitor cells as well as rat embryonic cortical neurons Zika virus (ZIKV) infection leads to ribosomal stress that is characterized by structural disruption of the nucleolus. The anti-nucleolar effects were most pronounced in postmitotic neurons. Moreover, in the latter system, nucleolar presence of ZIKV capsid protein (ZIKV-C) was associated with ribosomal stress and apoptosis. Deletion of 22 C-terminal residues of ZIKV-C prevented nucleolar localization, ribosomal stress and apoptosis. Consistent with a casual relationship between ZIKV-C-induced ribosomal stress and apoptosis, ZIKV-C-overexpressing neurons were protected by loss-of-function manipulations targeting the ribosomal stress effector Tp53 or knockdown of the ribosomal stress mediator RPL11. Finally, capsid protein of Dengue virus, but not West Nile virus, induced ribosomal stress and apoptosis. Thus, anti-nucleolar and pro-apoptotic effects of protein C are flavivirus-species specific. In the case of ZIKV, capsid protein-mediated ribosomal stress may contribute to neuronal death, neurodevelopmental disruption and microcephaly.

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

“…The nucleolus is prominently present in both NPCs and neurons (Hetman and Pietrzak ; Slomnicki et al . ). In many types of rapidly dividing cells efficient ribosomal biogenesis is required for proliferation by supplying ribosomes and suppressing RS (Tsai and Pederson ; Kusnadi et al .…”

“…Indeed, RS, as revealed by disruption of nucleolar NPM1 staining, preceded ZIKV‐induced apoptosis of the infected cultured cortical neurons from rat embryos (Slomnicki et al . ). Both responses were observed after infection with either the prototype ZIKV strain (African strain MR766) or a contemporary, Asian lineage ZIKV isolate (the 2015 Puerto Rico isolate PRVABC59) that has an established causative link to human microcephaly unlikely the African lineage (Lanciotti et al .…”

Tick-borne encephalitis virus inhibits rRNA synthesis and host protein production in human cells of neural origin

“…Tick-borne encephalitis virus and host rRNA/protein shut-off resulted in an increased rate of apoptosis via the p53 signalling cascade [64]. However, no disruption of nucleoli was observed in the case of TBEV-infected DAOY cells (S5B Fig), possibly not surprising as the TBEV infection specifically affects only the POLR1 activity.…”

Research advancements in the neurological presentation of flaviviruses

“…Further, ZIKV particles have been detected in the nucleoplasmic compartment, and the nuclear membrane was disrupted in ZIKV infections (Figure ), which has not been seen with DENV . In addition, ZIKV capsid protein causes ribosomal stress . Changes in intracellular membrane structures may be one mechanism by which ZIKV causes serious neuropathy.…”

“…65 In addition, ZIKV capsid protein causes ribosomal stress. 66 Changes in intracellular membrane structures may be one mechanism by which ZIKV causes serious neuropathy. ( Figure 6).…”