The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein Interacts with CDK1 To Induce G ₂ Cell Cycle Arrest and Positively Regulate Viral Replication

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. While many viruses subvert the host cell cycle to promote viral growth, it is unknown whether this is a strategy employed by SFTSV. In this study, we investigated how SFTSV manipulates the cell cycle and the effect of the host cell cycle on SFTSV replication. Our results suggest that cells arrest at the G2/M transition following infection with SFTSV. The accumulation of cells at the G2/M transition did not affect virus adsorption and entry but did facilitate viral replication. In addition, we found that SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells and promotes virulence by modulating the interferon response, induces a large number of cells to arrest at the G2/M transition by interacting with CDK1. The interaction between NSs and CDK1, which is inclusion body dependent, inhibits formation and nuclear import of the cyclin B1-CDK1 complex, thereby leading to cell cycle arrest. Expression of a CDK1 loss-of-function mutant reversed the inhibitive effect of NSs on the cell cycle, suggesting that this protein is a potential antiviral target. Our study provides new insight into the role of a specific viral protein in SFTSV replication, indicating that NSs induces G2/M arrest of SFTSV-infected cells, which promotes viral replication. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne pathogen that causes severe hemorrhagic fever. Although SFTSV poses a serious threat to public health and was recently isolated, its pathogenesis remains unclear. In particular, the relationship between SFTSV infection and the host cell cycle has not been described. Here, we show for the first time that both asynchronized and synchronized SFTSV-susceptible cells arrest at the G2/M checkpoint following SFTSV infection and that the accumulation of cells at this checkpoint facilitates viral replication. We also identify a key mechanism underlying SFTSV-induced G2/M arrest, in which SFTSV NSs interacts with CDK1 to inhibit formation and nuclear import of the cyclin B1-CDK1 complex, thus preventing it from regulating cell cycle progression. Our study highlights the key role that NSs plays in SFTSV-induced G2/M arrest.

A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins

“…Lastly, SFTSV NSs functions to increase virulence independent of the IFN systems. This includes upregulating the p62-Keap1-Nrf2 antioxidant pathway [ 144 ], inducing interleukin 10 (IL-10) expression involved in host immune response [ 145 ], suppressing NF-κB promoter activities to avoid innate immunity signaling [ 146 ], interacting with TRIM25 to mediate antiviral signaling [ 147 ], and promoting cell cycle arrest [ 148 ]. Further, although SFTSV NSs is dispensable for viral replication [ 128 ], it can form viroplasm-like structures (VLSs) in infected cells and these serve as sites of viral dsRNA localization, indicating a potential novel role of NSs in enhancing SFTSV replication [ 149 ].…”

A Mini-Review on Cell Cycle Regulation of Coronavirus Infection

“…The direct interaction between viral and host proteins is one of the effective strategies used by virus to manipulate the host cell cycle (40,41). CoVs can subvert the host cell cycle to facilitate viral replication through its interactions with host proteins.…”

Enzyme-Antibody-Modified Gold Nanoparticle Probes for the Ultrasensitive Detection of Nucleocapsid Protein in SFTSV

“…Between 2007 and 2010, a severe febrile illness was associated with gastrointestinal symptoms, thrombocytopenia, leukocytopenia, and high mortality in the eastern and central regions of China [1,2]. This disease is called severe fever with thrombocytopenia syndrome (SFTS) and was caused by the newly discovered bunyavirus (SFTSV) [3].…”