TY - JOUR
T1 - Structural basis for STAT2 suppression by flavivirus NS5
AU - Wang, Boxiao
AU - Thurmond, Stephanie
AU - Zhou, Kang
AU - Sánchez-Aparicio, Maria T.
AU - Fang, Jian
AU - Lu, Jiuwei
AU - Gao, Linfeng
AU - Ren, Wendan
AU - Cui, Yanxiang
AU - Veit, Ethan C.
AU - Hong, Hea Jin
AU - Evans, Matthew J.
AU - O’Leary, Seán E.
AU - García-Sastre, Adolfo
AU - Zhou, Z. Hong
AU - Hai, Rong
AU - Song, Jikui
N1 - Funding Information:
This work was supported by a UC Cancer Research Coordinating Committee Faculty Seed Grant (CRR-20-634140) to J.S., and the NIH (1R35GM119721 to J.S, 1R21AI147057 to J.S. and R.H., R01GM071940 to Z.H.Z., R21 AI133649 to M.J.E. and R00GM111858 to S.E.O.). This work is also partly funded by the Trans fund of the State of California (AB2664) to J.S. and R.H, and by DHIPC (Dengue Human Immunology Project Consortium) and a NIAID funded program (U19AI118610) to A.G.-S. M.J.E. holds Investigator in Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund. K.Z. was partially supported by a fellowship from the China Scholarship Council. We acknowledge the assistance of D. Carter for microscopy imaging. Microscopy and/or image analysis was also performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai. We thank G. Tan for assisting with statistical analysis on the growth-curve data. We also acknowledge the use of instruments at the Electron Imaging Center for Nanomachines supported by UCLA and by instrumentation grants from NIH (1S10RR23057, 1S10OD018111 and U24GM116792) and NSF (DBI-1338135 and DMR-1548924). We would like to thank staff members at the Advanced Light Source, Lawrence Berkeley National Laboratory, for access to X-ray beamlines. The Advanced Light Source is supported by the director, office of science, office of basic energy sciences, of the US Department of Energy under contract no. DE-AC02-05CH11231. We thank S. Ding and D. Bogunovic for providing the DENV cDNA clone and VSV–GFP virus, respectively. We also thank Z. Hu for insightful discussions.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of structural information about the viral–cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved interdomain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the amino-terminal domain of hSTAT2. Disruption of these ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent conditions. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.
AB - Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of structural information about the viral–cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved interdomain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the amino-terminal domain of hSTAT2. Disruption of these ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent conditions. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.
UR - http://www.scopus.com/inward/record.url?scp=85089175462&partnerID=8YFLogxK
U2 - 10.1038/s41594-020-0472-y
DO - 10.1038/s41594-020-0472-y
M3 - Article
C2 - 32778820
AN - SCOPUS:85089175462
SN - 1545-9993
VL - 27
SP - 875
EP - 885
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 10
ER -