The Host DHX9 DExH-Box Helicase Is Recruited to Chikungunya Virus Replication Complexes for Optimal Genomic RNA Translation

Roy Matkovic (1) , Eric Bernard (1) , Simon Fontanel (1) , Patrick Eldin (1) , Nathalie Chazal (1) , Deka Hassan Hersi (1) , Andres Merits (2) , Jean-Marie Peloponese (1) , Laurence Briant (1)

1 IRIM - Institut de Recherche en Infectiologie de Montpellier
2 University of Tartu

Beyond their role in cellular RNA metabolism, DExD/H-box RNA heli-cases are hijacked by various RNA viruses in order to assist replication of the viral genome. Here, we identify the DExH-box RNA helicase 9 (DHX9) as a binding partner of chikungunya virus (CHIKV) nsP3 mainly interacting with the C-terminal hypervari-able domain. We show that during early CHIKV infection, DHX9 is recruited to the plasma membrane, where it associates with replication complexes. At a later stage of infection, DHX9 is, however, degraded through a proteasome-dependent mechanism. Using silencing experiments, we demonstrate that while DHX9 negatively controls viral RNA synthesis, it is also required for optimal mature nonstructural protein translation. Altogether, this study identifies DHX9 as a novel cofactor for CHIKV repli-cation in human cells that differently regulates the various steps of CHIKV life cycle and may therefore mediate a switch in RNA usage from translation to replication during the earliest steps of CHIKV replication. IMPORTANCE The reemergence of chikungunya virus (CHIKV), an alphavirus that is transmitted to humans by Aedes mosquitoes, is a serious global health threat. In the absence of effective antiviral drugs, CHIKV infection has a significant impact on human health, with chronic arthritis being one of the most serious complications. The molecular understanding of host-virus interactions is a prerequisite to the development of targeted therapeutics capable to interrupt viral replication and transmission. Here, we identify the host cell DHX9 DExH-Box helicase as an essential cofactor for early CHIKV genome translation. We demonstrate that CHIKV nsP3 protein acts as a key factor for DHX9 recruitment to replication complexes. Finally, we establish that DHX9 behaves as a switch that regulates the progression of the viral cycle from translation to genome replication. This study might therefore have a significant impact on the development of antiviral strategies. KEYWORDS chikungunya virus, DHX9, RNA helicase, nsP3, viral replication T he chikungunya virus (CHIKV), a mosquito-borne alphavirus transmitted by Aedes mosquitoes, represents an ongoing challenge to medicine and public health. The clinical manifestation of CHIKV infection is an acute syndrome (high fever, rash, myalgia, and intense arthralgia) that coincides with high viremia. In the absence of targeted therapeutics the infection evolves into a chronic incapacitating arthralgia in the distal joints in more than half of the cases, with patients requiring long-term administration of anti-inflammatory and immunosuppressive treatment (for a review, see reference 1). Because CHIKV recently caused major outbreaks worldwide with a disastrous socioeconomic impact and because antiviral molecules are still lacking, there is an urgent need to identify the mechanisms of infection that might be targeted therapeutically. Citation Matkovic R, Bernard E, Fontanel S, Eldin P, Chazal N, Hassan Hersi D, Merits A, Péloponèse J-M, Briant L. 2019. The host DHX9 DExH-box helicase is recruited to chikungunya virus replication complexes for optimal genomic RNA translation. J Virol 93:e01764-18.

Domaines: Virologie

Roy Matkovic, Eric Bernard, Simon Fontanel, Patrick Eldin, Nathalie Chazal, et al.. The Host DHX9 DExH-Box Helicase Is Recruited to Chikungunya Virus Replication Complexes for Optimal Genomic RNA Translation. Journal of Virology, 2019, 93 (4), pp.1764 - 1782. ⟨10.1128/JVI.01764-18⟩. ⟨hal-02147108⟩