Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Li, Hongda; Saucedo-Cuevas, Laura; Yuan, Ling; Ross, Danica; Johansen, Anide; Sands, Daniel I.; Stanley, Valentina; Guemez‐Gamboa, Alicia; Gregor, Anne; Evans, Todd; Chen, Shuibing; Tan, Lianjiang; Molina, Henrik; Sheets, Nicholas; Shiryaev, Sergey A.; Terskikh, Alexey V.; Gladfelter, Amy S.; Shresta, Sujan; Xu, Zhiheng; Gleeson, Joseph G.

doi:10.1016/j.neuron.2019.01.010

Cited by 65 publications

(62 citation statements)

References 66 publications

(76 reference statements)

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“…Beyond a genetic basis, microcephaly is also caused by viral infection, notably Cytomegalovirus or Zika virus (ZIKV) infection during pregnancy [25]. Several studies have shown that acute ZIKV infection can also impair neural progenitor mitosis and in some cases is associated with aberrant neurogenesis and apoptosis in human and mouse models [26][27][28][29]. Thus, both genetic and viral causes of microcephaly are linked to progenitor mitosis defects and similar alterations in neurogenesis and cell survival.…”

Section: Introductionmentioning

confidence: 99%

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

et al. 2019

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Background/Aims: Prenatal microcephaly is posited to arise from aberrant mitosis of neural progenitors, which disrupts both neuronal production and survival. Although microcephaly has both a genetic and environmental etiology, the mechanisms by which dysregulation of mitosis causes microcephaly are poorly understood. We previously discovered that prolonged mitosis of mouse neural progenitors, either ex vivo or in vitro, directly alters progeny cell fate, resulting in precocious differentiation and apoptosis. This raises questions as to whether prolonged progenitor mitosis affects cell fate and neurogenesis in vivo, and what are the underlying mechanisms? Methods/Results: Towards addressing these knowledge gaps, we developed an in vivo model of mitotic delay. This uses pharmacological inhibition to acutely and reversibly prolong mitosis during cortical development, and fluorescent dyes to label direct progeny. Using this model, we discovered that a causal relationship between mitotic delay of neural progenitors and altered progeny cell fate is evident in vivo. Using transcriptome analyses to investigate the state of delayed cells and their progeny, we uncovered potential molecular mechanisms by which prolonged mitosis induces altered cell fates, including DNA damage and p53 signaling. We then extended our studies to human neural progenitors, demonstrating that lengthened mitosis duration also directly alters neuronal cell fate. Conclusions: This study establishes a valuable new experimental paradigm towards understanding mechanisms whereby lengthened mitosis duration may explain some cases of microcephaly.

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Section: Introductionmentioning

confidence: 99%

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

et al. 2019

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“…Previous data showed that NS4AB interferes with the mTOR pathway in NPCs, reducing proliferation and inducing autophagy 45 , and that NS2A interacts with AJs, while disrupting the integrity of the developing neuroepithelium and again, perturbing NPC proliferation 20 . Recently, the NS2B3 heterodimer was also shown to disturb the cell-cycle as it affects the host protein Septin-2 that is involved in NPCs cytokinesis 46 . To date, NS5 has only been shown to counteract host antiviral mechanisms by targeting the interferon pathway 47 .…”

Section: Discussionmentioning

confidence: 99%

Multimerization of Zika Virus-NS5 causes a ciliopathy and forces premature neurogenesis

Saade

Ferrero

Blanco-Ameijeiras

et al. 2019

Preprint

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33Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital 34 microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and 35 enhance cell death, although the underlying cellular events involved remain unclear. 36 Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the 37 primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and 38 premature neuron delamination. Furthermore, in human microcephalic fetal brain 39 tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which also 40 exhibit a severe ciliopathy. While the enzymatic activity of ZikV-NS5 appears to be 41 dispensable, the Y25, K28 and K29 residues in the protein, that are involved in NS5-42 oligomerization, are essential for the localization and interaction with components of the 43 cilium base, promoting ciliopathy and premature neurogenesis. These findings lay the 44 foundation to develop therapies that target ZikV-NS5-multimerization, preventing the 45 developmental malformations associated with congenital Zika syndrome 46 47 48 Zika virus (ZikV) is a flavivirus transmitted by the bite of the Aedes mosquito 1 . The 11 49 kb positive-sense, single-stranded RNA genome of ZikV encodes ten mature viral 50 proteins: three structural proteins (C, prM and E) and seven non-structural proteins 51 (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) 1 . A single amino acid substitution 52 (S139N) in prM seems to be responsible for the change in virus tropism that provokes a 53 dramatic increase in neonatal microcephaly 22 , and that has led to this virus being 54 declared a global threat to public health. ZikV can directly infect human neural 55 progenitor cells (NPCs) in both 2D and 3D in vitro models of the developing cerebral 56 cortex, resulting in defects resembling congenital microcephaly 3-8 . However, the 57 mechanisms by which ZikV disrupts neurogenesis have not yet been fully elucidated. 58Moreover, macaque monkey infection provokes regional disturbances in the brain that 59 impair postnatal neurogenesis, provoking cognitive deficits and epilepsy 9 . This 60 vulnerability of late neurogenic regions to ZikV also persists in adult mice 10 . As it is 61 well known that human brain development extends for many years beyond birth and 62 that adult neurogenesis influences cognitive functions, it is no longer safe to consider 63 ZikV as a transient infection in adult humans without marked long-term effects. 64 65 The limited availability of human tissue to perform histological analyses at different 66 developmental stages 11 emphasizes the need to use in vivo animal models to understand 67 congenital Zika syndrome. Here we used the chick embryo neural tube (NT) to screen 68 non-structural (NS) ZikV protein components and assess their impact on neurogenesis, 69 particularly given that this in vivo model has served to identify fundamental processes in 70 mammalian neural development and human disease. Through this approach, ZikV-NS5 71 w...

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“…Considering the role of septins in membrane curvature recognition, it would be interesting to address whether recruitment of septins to sites where CEV fuses with the plasma membrane depends on membrane curvature. Interestingly, new work has shown that the protease NS2B-NS3 heterodimer from Zika virus, a mosquito-transmitted Flavivirus that causes microcephaly, can mediate cytokinesis defects and cell death through cleavage of SEPT2 (Li et al, 2019). The role of septins in infection by other pathogenic viruses has not yet been tested.…”

Section: Septin Entrapment Of Vaccinia Virusmentioning

confidence: 99%

Role of septins in microbial infection

Ngo

Mostowy

2019

Journal of Cell Science

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Septins are widely recognized as a component of the cytoskeleton that is essential for cell division, and new work has shown that septins can recognise cell shape by assembling into filaments on membrane regions that display micrometer-scale curvature (e.g. at the cytokinetic furrow). Moreover, infection biology studies have illuminated important roles for septins in mediating the outcome of host-microbe interactions. In this Review, we discuss a selection of mechanistic insights recently gained from studying three infection paradigms: the rice blast fungus Magnaporthe oryzae, the poxvirus family member vaccinia virus and the Gram-negative bacterium Shigella flexneri. These studies have respectively discovered that higher-order septin assemblies enable fungal invasion into plant cells, entrap viral particles at the plasma membrane and recognize dividing bacterial cells for delivery to lysosomes. Collectively, these insights illustrate how studying septin biology during microbial infection can provide fundamental advances in both cell and infection biology, and suggest new concepts underlying infection control.

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Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors

Cited by 65 publications

References 66 publications

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

Multimerization of Zika Virus-NS5 causes a ciliopathy and forces premature neurogenesis

Role of septins in microbial infection

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