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Phase transition and amyloid formation by a viral protein as an additional molecular mechanism of virus-induced cell toxicity

Edoardo Salladini, Claire Debarnot, Vincent Delauzun, Maria Grazia Murrali, Priscila Sutto-Ortiz, Silvia Spinelli, Roberta Pierattelli, Christophe Bignon, Sonia Longhi
doi: https://doi.org/10.1101/497024
Edoardo Salladini
1Aix-Marseille Univ, CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Marseille, France
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Claire Debarnot
1Aix-Marseille Univ, CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Marseille, France
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Vincent Delauzun
1Aix-Marseille Univ, CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Marseille, France
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Maria Grazia Murrali
2Magnetic Resonance Center (CERM), Department of Chemistry “Ugo Schiff” Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
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Priscila Sutto-Ortiz
1Aix-Marseille Univ, CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Marseille, France
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Silvia Spinelli
1Aix-Marseille Univ, CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Marseille, France
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Roberta Pierattelli
2Magnetic Resonance Center (CERM), Department of Chemistry “Ugo Schiff” Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy
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Christophe Bignon
1Aix-Marseille Univ, CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Marseille, France
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Sonia Longhi
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  • For correspondence: Sonia.Longhi@afmb.univ-mrs.fr
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Abstract

Henipaviruses are severe human pathogens responsible for severe encephalitis. Their V protein is a key player in the evasion of the host innate immune response. We have previously reported a biophysical characterization of the Henipavirus V proteins and shown that they interact with DDB1, a cellular protein that is a component of the ubiquitin ligase E3 complex. Here, we serendipitously discovered that the Hendra virus V protein undergoes a liquidhydrogel phase transition. By combining experimental and bioinformatics approaches, we have identified the V region responsible for this phenomenon. This region (referred to as PNT3), which falls within the long intrinsically disordered region of V, was further investigated using a combination of biophysical and structural approaches. ThioflavinT and Congo red binding assays, together with negative-staining electron microscopy studies, show that this region forms amyloid-like, β-enriched structures. Such structures are also formed in mammal cells transfected to express PNT3. Those cells also exhibit a reduced viability in the presence of a stress agent. Interestingly, mammal cells expressing a rationally designed, non-amyloidogenic PNT3 variant (PNT33A), appear to be much less sensitive to the stress agent, thus enabling the establishment of a link between fibril formation and cell toxicity. The present findings therefore pinpoint a so far never reported possible mechanism of virus-induced cell toxicity.

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Posted December 14, 2018.
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Phase transition and amyloid formation by a viral protein as an additional molecular mechanism of virus-induced cell toxicity
Edoardo Salladini, Claire Debarnot, Vincent Delauzun, Maria Grazia Murrali, Priscila Sutto-Ortiz, Silvia Spinelli, Roberta Pierattelli, Christophe Bignon, Sonia Longhi
bioRxiv 497024; doi: https://doi.org/10.1101/497024
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Phase transition and amyloid formation by a viral protein as an additional molecular mechanism of virus-induced cell toxicity
Edoardo Salladini, Claire Debarnot, Vincent Delauzun, Maria Grazia Murrali, Priscila Sutto-Ortiz, Silvia Spinelli, Roberta Pierattelli, Christophe Bignon, Sonia Longhi
bioRxiv 497024; doi: https://doi.org/10.1101/497024

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