| Author's Name |
Priya S. Shah, Nichole Link, Gwendolyn M. Jang, Phillip P. Sharp, Tongtong Zhu, ââ¬Â¨Danielle L. Swaney, Jeffrey R. Johnson, John Von Dollen, Holly R. Ramage, Laura Satkamp, ââ¬Â¨Billy Newton, Ruth Huttenhain, Marine J. Petit, Tierney Baum, Amanda Everitt, Orly Laufman, ââ¬Â¨Michel Tassetto, Michael Shales, Erica Stevenson, Gabriel N. Iglesias, Leila Shokat, Shashank Tripathi, Vinod Balasubramaniam, Laurence G. Webb, Sebastian Aguirre,8 A. Jeremy Willsey, Adolfo Garcia-Sastre, Katherine S. Pollard, Sara Cherry, Andrea V. Gamarnik, Ivan Marazzi, Jack Taunton, ââ¬Â¨Ana Fernandez-Sesma, Hugo J. Bellen, Raul Andino, and Nevan J. Krogan |
| Abstract |
Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-hostinteractions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirusNS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKVspecific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms. |
