PT - JOURNAL ARTICLE AU - Salladini, Edoardo AU - Debarnot, Claire AU - Delauzun, Vincent AU - Murrali, Maria Grazia AU - Sutto-Ortiz, Priscila AU - Spinelli, Silvia AU - Pierattelli, Roberta AU - Bignon, Christophe AU - Longhi, Sonia TI - Phase transition and amyloid formation by a viral protein as an additional molecular mechanism of virus-induced cell toxicity AID - 10.1101/497024 DP - 2018 Jan 01 TA - bioRxiv PG - 497024 4099 - http://biorxiv.org/content/early/2018/12/14/497024.short 4100 - http://biorxiv.org/content/early/2018/12/14/497024.full AB - 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.