Phase transition and amyloid formation by a viral protein as an additional molecular mechanism of virus-induced cell toxicity
| Autor: | C. Debarnot, Vincent Delauzun, Sonia Longhi, Roberta Pierattelli, Silvia Spinelli, Christophe Bignon, Priscila Sutto-Ortiz, Maria Grazia Murrali, Edoardo Salladini |
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| Přispěvatelé: | Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bioénergétique et Ingénierie des Protéines (BIP ), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Dept Chem Ugo Schiff, University of Florence (UNIFI), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Università degli Studi di Firenze = University of Florence (UniFI) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Innate immune system Amyloid biology [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Chemistry Viral protein 030302 biochemistry & molecular biology [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Transfection medicine.disease_cause biology.organism_classification Virus Cell biology [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biophysics 03 medical and health sciences DDB1 [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] medicine Hendra Virus [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] 030304 developmental biology Henipavirus |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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