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The Nonstructural Protein of Guertu Virus Disrupts Host Defenses by Blocking Antiviral Interferon Induction and Action
journal contribution
posted on 2020-03-20, 17:53 authored by Yuan-Qin Min, Chen Shi, Ting Yao, Kuan Feng, Qiong Mo, Fei Deng, Hualin Wang, Yun-Jia NingGuertu virus (GTV)
is a potentially highly pathogenic bunyavirus newly isolated in China,
which is genetically related to the severe fever with thrombocytopenia
syndrome virus (SFTSV) and Heartland virus (HRTV), two other emerging
life-threatening bunyaviruses. Previous studies suggested that SFTSV
and HRTV antagonize the interferon (IFN) system by targeting antiviral
signaling proteins in different ways. However, whether and how GTV
counteracts the host innate immunity are unclear. Here, we found that
GTV strongly inhibits both IFN induction and action through its nonstructural
protein (NSs). Different from the NSs of SFTSV and HRTV, GTV NSs (G-NSs)
induced the formation of two distinctive cytoplasmic structures, compact
inclusion bodies (IBs) and extended filamentous structures (FSs).
Protein interaction and colocalization analyses demonstrated that
G-NSs interacts with TBK1 (TANK binding kinase-1, the pivotal kinase
for IFN induction) and STAT2 (signal transducer and activator of transcription
2, the essential transcription factor for IFN action) and irreversibly
sequesters the host proteins into the viral IBs and FSs. Consistently,
G-NSs thus inhibited phosphorylation/activation and nuclear translocation
of IFN-regulatory factor 3 (IRF3, the substrate of TBK1), diminishing
the IFN induction. Furthermore, G-NSs sequestration of STAT2 blocked
phosphorylation/activation and nuclear translocation of STAT2, disabling
IFN action and host antiviral state establishment. Collectively, this
study shows the robust subversion of the two phases of the IFN antiviral
system by GTV and unravels the respective molecular mechanisms, exhibiting
some notable differences from those employed by SFTSV and HRTV, providing
insights into the virus–host interactions and pathogenesis,
and probably also benefiting the prevention and treatment of the related
infectious diseases in the future.