Viral RNA switch mediates the dynamic control of flavivirus replicase recruitment by genome cyclization.
Viral replicase recruitment and long-range RNA interactions are essential for RNA virus replication, yet the mechanism of their interplay remains elusive. Flaviviruses include numerous important human pathogens, e.g., dengue virus (DENV) and Zika virus (ZIKV). Here, we revealed a highly conserved, conformation-tunablecis-acting element named 5'-UAR-flanking stem (UFS) in the flavivirus genomic 5' terminus. We demonstrated that the UFS was critical for efficient NS5 recruitment and viral RNA synthesis in different flaviviruses. Interestingly, stabilization of the DENV UFS impaired both genome cyclization and vRNA replication. Moreover, the UFS unwound in response to genome cyclization, leading to the decreased affinity of NS5 for the viral 5' end. Thus, we propose that the UFS is switched by genome cyclization to regulate dynamic RdRp binding for vRNA replication. This study demonstrates that the UFS enables communication between flavivirus genome cyclization and RdRp recruitment, highlighting the presence of switch-like mechanisms among RNA viruses.
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
Zhong-Yu
ZY
Liu
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
Xiao-Feng
XF
Li
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
Tao
T
Jiang
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
Yong-Qiang
YQ
Deng
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Qing
Q
Ye
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Hui
H
Zhao
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Jiu-Yang
JY
Yu
Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|State Key Laboratory of Pathogen and Biosecurity, Beijing, China.
Cheng-Feng
0000-0002-0632-2807
CF
Qin
D020121:5' Untranslated Regions; D003500:Cyclization; D005416:Flavivirus / Q000502:physiology*; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
D020121:5' Untranslated Regions; C096041:NS5 protein, flavivirus; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase
biochemistry; cis-acting element; flavivirus; genome cyclization; infectious disease; microbiology; viral RNA structure; viral replicase recruitment; virus
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