Structural elucidation of viral antagonism of innate immunity: the STAT1 interface

摘要: To evade innate immunity, many viruses express interferon-antagonists that target STATs, critical mediators of immune signalling. Virus-STAT interfaces may provide new therapeutic targets but progress is hindered by a lack direct structural data, owing to poor tractability antagonists/full-length STATs for structural/biophysical approaches. By applying cross-saturation transfer NMR, we report the first analysis binding full-length STAT1 an interferon-antagonist human pathogenic virus, such study virus-host interface. Analysis using mutation interface, biophysical characterization, signalling/protein-protein interaction assays including PCA, reverse genetics and animal infection demonstrated significance this interface in signaling suppression, disease caused field-strain lyssavirus. Importantly, NMR/mutagenesis also revealed comprises multiple surfaces/domains both viral cellular partners, indicating antagonism involves extensive interactions consistent with multifaceted inhibitory mechanism, distinct from ‘simple’ mechanisms as tethering. Furthermore, elucidating spatial relationship evasion replication, data insight into how ostensibly simple can regulate these central functions via single multifunctional protein. These novel insights fundamental biology, potential exploitation antivirals vaccine development. The demonstrates power biophysical/NMR approaches elucidate atomic regulatory proteins, providing framework studies reveal other pathogens their full complexity.