%0 Journal Article %T Lyssavirus P-protein selectively targets STAT3-STAT1 heterodimers to modulate cytokine signalling %+ Monash University [Clayton] %+ University of Melbourne %+ Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology %+ Gifu University %A Harrison, Angela %A Lieu, Kim %A Larrous, Florence %A Ito, Naoto %A Bourhy, Hervé %A Moseley, Gregory %Z This research was supported by National Health and Medical Research Council Australia project grants 1125704 and 1079211 (G.W.M and H.B.) https://www.nhmrc.gov.au/, Australian Research Council discovery project grant DP150102569 (G.W.M) https://www.arc.gov.au/, Miegunyah Trust Grimwade Fellowship (G.W.M), and Australian Government Research Training Program Scholarship (A.R.H) https://www.education.gov.au/research-training-program. %< avec comité de lecture %@ 1553-7366 %J PLoS Pathogens %I Public Library of Science %V 16 %N 9 %P e1008767 %8 2020-09-09 %D 2020 %R 10.1371/journal.ppat.1008767 %M 32903273 %Z Life Sciences [q-bio]Journal articles %X Many viruses target signal transducer and activator of transcription (STAT) 1 to antagonise antiviral interferon signalling, but targeting of STAT3, a pleiotropic molecule that mediates signalling by diverse cytokines, is poorly understood. Here, using lyssavirus infection, quantitative live cell imaging, innate immune signalling and protein interaction assays, and complementation/depletion of STAT expression, we show that STAT3 antagonism is conserved among P-proteins of diverse pathogenic lyssaviruses and correlates with pathogenesis. Importantly, P-protein targeting of STAT3 involves a highly selective mechanism whereby P-protein antagonises cytokine-activated STAT3-STAT1 heterodimers, but not STAT3 homodimers. RT-qPCR and reporter gene assays indicate that this results in specific modulation of interleukin-6-dependent pathways, effecting differential antagonism of target genes. These data provide novel insights into mechanisms by which viruses can modulate cellular function to support infection through discriminatory targeting of immune signalling complexes. The findings also highlight the potential application of selective interferon-antagonists as tools to delineate signalling by particular STAT complexes, significant not only to pathogen-host interactions but also cell physiology, development and cancer. %G English %Z We acknowledge Cassandra David for assistance with tissue culture, and the facilities and technical assistance of the Biological Optical Microscopy Platform (University of Melbourne), Monash Micro Imaging Facility (Monash University) and Unité de Technologie et service Biolmagerie Photonique (Institut Pasteur). Plasmids to express STAT3-mCherry and Mumps V-FLAG were kind gifts from Marie Bogoyevitch (University of Melbourne) and Curt Horvath (Addgene plasmid #44908), respectively. pEBTetD plasmid for inducible protein expression was a kind gift from Dirk Gründemann (University of Cologne). U3A and 2fTGH cells were a kind gift from George Stark (Lerner Research Institute, Cleveland Clinic). %2 https://pasteur.hal.science/pasteur-03921193/document %2 https://pasteur.hal.science/pasteur-03921193/file/document15.pdf %L pasteur-03921193 %U https://pasteur.hal.science/pasteur-03921193 %~ PASTEUR