Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis

Abstract

Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear.Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also exhibit a severe ciliopathy. While the enzymatic activity of ZikV-NS5 appears to be dispensable, the Y25, K28 and K29 residues in the protein, that are involved in NS5oligomerization, are essential for the localization and interaction with components of the cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the foundation to develop therapies that target ZikV-NS5-multimerization, preventing the developmental malformations associated with congenital Zika syndrome

Zika Virus Infection Prevents Host mRNA Nuclear Export by Disrupting UPF1 Function

“…NPCs are critical for brain development as they differentiate into the glial and neuronal cells that compose the majority of the brain parenchyma (Martínez-Cerdeño & Noctor, 2018). Proposed molecular mechanisms by which ZIKV disrupts NPC function and differentiation include perturbation of ANKLE2/VRK1, centrosomal organization, autophagy, apoptosis and unfolded protein response pathways (Link et al, 2019; Ojha et al, 2018; Saade et al, 2020; Shah et al, 2018; Wen et al, 2019). However, it remains unknown how ZIKV manipulates multiple cellular pathways at once to cause such widespread developmental reprogramming.…”

Zika Virus and Neuropathogenesis: The Unanswered Question of Which Strain Is More Prone to Causing Microcephaly and Other Neurological Defects

“…Recent studies have shown that ZIKV is also able to induce premature differentiation of NPCs into mature neurons ( Gabriel et al, 2017 ; Saade et al, 2020 ). Notably, the levels of generated mature neurons did not accumulate and remained at a steady level, indicating that ZIKV is able to trigger differentiation of NPCs and then induce apoptosis of the newly generated neurons ( Gabriel et al, 2017 ).…”

“…During asymmetric division, the daughter cell inheriting the mature centriole reforms the primary cilia, thus maintaining attachment to the ventricular surface and the status as an NPC. The other daughter cell will not reform a primary cilium, and will thus undergo delamination, basal migration and maturation into a neuron ( Figure 6 ) ( Gilmore and Walsh, 2013 ; Saade et al, 2020 ). Inheritance of the mature centriole is key to reforming the primary cilium, as it forms the core of the primary cilium basal body structure, and associates with Cep164 centrosomal protein to allow primary cilia assembly ( Graser et al, 2007 ).…”

“…During asymmetric division of apical NPCs, the daughter cell that reforms the primary cilia remains attached to the ventricular surface whereas the other daughter cell that does not undergo ciliogenesis delaminates from the ventricular surface and differentiates. ZIKV NS5 protein interacts with cellular proteins at the base of the primary cilia in NPCs causing an atypical ciliopathy and premature neuron delamination (adapted from Saade et al, 2020 , created with Biorender.com ).…”

“…Infection of the developing foetal brain with ZIKV results in shorter cilia being reformed following NPC division. This is mediated specifically by the viral polymerase (NS5) ( Saade et al, 2020 ). NPCs electroporated with NS5 and no other viral NS proteins exhibit significantly reduced cilia lengths.…”