Erratum: ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly and p53

Abstract Epidemiological evidence from the current outbreak of Zika virus (ZIKV) and recent studies in animal models indicate a strong causal link between ZIKV and microcephaly. ZIKV infection induces cell-cycle arrest and apoptosis in proliferating neural progenitors. However, the mechanisms leading to these phenotypes are still largely obscure. In this report, we explored the possible similarities between transcriptional responses induced by ZIKV in human neural progenitors and those elicited by three different genetic mutations leading to severe forms of microcephaly in mice. We found that the strongest similarity between all these conditions is the activation of common P53 downstream genes. In agreement with these observations, we report that ZIKV infection increases total P53 levels and nuclear accumulation, as well as P53 Ser15 phosphorylation, correlated with genotoxic stress and apoptosis induction. Interestingly, increased P53 activation and apoptosis are induced not only in cells expressing high levels of viral antigens but also in cells showing low or undetectable levels of the same proteins. These results indicate that P53 activation is an early and specific event in ZIKV-infected cells, which could result from cell-autonomous and/or non-cell-autonomous mechanisms. Moreover, we highlight a small group of P53 effector proteins that could act as critical mediators, not only in ZIKV-induced microcephaly but also in many genetic microcephaly syndromes.

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

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735004711.793559572 ◽

2019 ◽

Author(s):

Serge Mostowy ◽

Stevens Robertin

Keyword(s):

Zika Virus ◽

Neural Progenitors ◽

Host Protein ◽

Protease Cleavage

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

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735004711.793558430 ◽

2019 ◽

Author(s):

Elias Spiliotis ◽

Eva Karasmanis

Keyword(s):

Zika Virus ◽

Neural Progenitors ◽

Host Protein ◽

Protease Cleavage

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SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

Nature Communications ◽

10.1038/s41467-021-24391-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Federica Banfi ◽

Alicia Rubio ◽

Mattia Zaghi ◽

Luca Massimino ◽

Giulia Fagnocchi ◽

...

Keyword(s):

Dna Damage ◽

Neuronal Death ◽

Neuronal Loss ◽

Genotoxic Stress ◽

Protein Product ◽

Neural Progenitors ◽

Cell Identity ◽

Neurodegenerative Process ◽

Parp 1 ◽

Shed Light

AbstractThe investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

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Zika Virus Infects Neural Progenitors in the Adult Mouse Brain and Alters Proliferation

Cell Stem Cell ◽

10.1016/j.stem.2016.08.005 ◽

2016 ◽

Vol 19 (5) ◽

pp. 593-598 ◽

Cited By ~ 147

Author(s):

Hongda Li ◽

Laura Saucedo-Cuevas ◽

Jose A. Regla-Nava ◽

Guoliang Chai ◽

Nicholas Sheets ◽

...

Keyword(s):

Mouse Brain ◽

Zika Virus ◽

Adult Mouse ◽

Neural Progenitors ◽

Adult Mouse Brain

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

Neuron ◽

10.1016/j.neuron.2019.01.010 ◽

2019 ◽

Vol 101 (6) ◽

pp. 1089-1098.e4 ◽

Cited By ~ 20

Author(s):

Hongda Li ◽

Laura Saucedo-Cuevas ◽

Ling Yuan ◽

Danica Ross ◽

Anide Johansen ◽

...

Keyword(s):

Zika Virus ◽

Neural Progenitors ◽

Host Protein ◽

Protease Cleavage

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Mechanisms of p53 activation and physiological relevance in the developing kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00642.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. F928-F940 ◽

Cited By ~ 7

Author(s):

Karam Aboudehen ◽

Sylvia Hilliard ◽

Zubaida Saifudeen ◽

Samir S. El-Dahr

Keyword(s):

Posttranslational Modifications ◽

Expression Patterns ◽

Genotoxic Stress ◽

Binding Activity ◽

Site Directed Mutagenesis ◽

Dna Binding Activity ◽

Nephron Progenitors ◽

P53 Activation ◽

Developing Kidney ◽

P53 Stability

The tumor suppressor protein p53 is a short-lived transcription factor due to Mdm2-mediated proteosomal degradation. In response to genotoxic stress, p53 is stabilized via posttranslational modifications which prevent Mdm2 binding. p53 activation results in cell cycle arrest and apoptosis. We previously reported that tight regulation of p53 activity is an absolute requirement for normal nephron differentiation (Hilliard S, Aboudehen K, Yao X, El-Dahr SS Dev Biol 353: 354–366, 2011). However, the mechanisms of p53 activation in the developing kidney are unknown. We show here that metanephric p53 is phosphorylated and acetylated on key serine and lysine residues, respectively, in a temporal profile which correlates with the maturational changes in total p53 levels and DNA-binding activity. Site-directed mutagenesis revealed a differential role for these posttranslational modifications in mediating p53 stability and transcriptional regulation of renal function genes (RFGs). Section immunofluorescence also revealed that p53 modifications confer the protein with specific spatiotemporal expression patterns. For example, phos-p53S392 is enriched in maturing proximal tubular epithelial cells, whereas acetyl-p53K373/K382/K386 are expressed in nephron progenitors. Functionally, p53 occupancy of RFG promoters is enhanced at the onset of tubular differentiation, and p53 loss or gain of function indicates that p53 is necessary but not sufficient for RFG expression. We conclude that posttranslational modifications are important determinants of p53 stability and physiological functions in the developing kidney. We speculate that the stress/hypoxia of the embryonic microenvironment may provide the stimulus for p53 activation in the developing kidney.

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TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m116.763318 ◽

2017 ◽

Vol 292 (8) ◽

pp. 3201-3212 ◽

Cited By ~ 4

Author(s):

Ryo Maeda ◽

Hiroyuki Tamashiro ◽

Kazunori Takano ◽

Hiro Takahashi ◽

Hidefumi Suzuki ◽

...

Keyword(s):

Cell Fate ◽

Nuclear Export ◽

Cellular Response ◽

P53 Protein ◽

Genotoxic Stress ◽

Negative Control ◽

Cell Fate Decisions ◽

Single Cell Imaging ◽

P53 Activation ◽

Induced Apoptosis

Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.

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A Possible Role Of Microglia In Zika Virus Infection Of The Fetal Human Brain

10.1101/142497 ◽

2017 ◽

Cited By ~ 1

Author(s):

Julien Muffat ◽

Yun Li ◽

Attya Omer ◽

Ann Durbin ◽

Irene Bosch ◽

...

Keyword(s):

Stem Cells ◽

Zika Virus ◽

Fetal Brain ◽

Cell Types ◽

Neural Progenitors ◽

Viral Reservoir ◽

Viral Reservoirs ◽

Viral Spread ◽

Brain Infection

Maternal Zika virus (ZIKV) infection during pregnancy is increasingly recognized as the cause of an epidemic of microcephaly and other neurological anomalies in human fetuses. However, it remains unclear how ZIKV gains access to the highly vulnerable population of neural progenitors of the fetal central nervous system (CNS), and which cell types of the CNS may serve as viral reservoirs. To model viral interaction with cells of the fetal CNS in vitro, we investigated the tropism of ZIKV for different iPS-derived human cells, with a particular focus on microglia-like cells derived from human pluripotent stem cells. We show that ZIKV infected isogenic neural progenitors, astrocytes and microglia-like cells, but was only cytotoxic to neural progenitors. Infected glial cells propagated the virus and maintained viral load over time, leading to viral spread to susceptible cells. ZIKV-infected microglia, when co-cultured with pre-established neural spheroids, invaded the tissue and initiated neural infection. Since microglia derive from primitive macrophages originating in anatomical proximity to the maternal vasculature of the placenta, we propose that they may act in vivo as a viral reservoir for ZIKV and, owing to their natural ability to traverse the embryo, can establish infection of the fetal brain. Infection of immature neural stem cells by invading microglia may occur in the early stages of pregnancy, before vascular circulation is established. Our data are also consistent with the virus affecting the integrity of the blood-brain barrier (BBB), which may allow infection of the brain at later stages.

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