Human cytomegalovirus induces and exploits Roquin to counteract the IRF1-mediated antiviral state

다국어 초록 (Multilingual Abstract)

<P><B>Significance</B></P><P>Human cytomegalovirus (HCMV) is a major cause of birth defects and diseases in immune-compromised patients. HCMV is able to infect and establish latency in large populations by employing multiple strategies to evading the host immune response. Here, we report that HCMV suppresses cytokine-mediated antiviral responses by increasing the expression of cellular RNA-binding protein, Roquin. We show that Roquin inhibits cytokine production by directly binding to cytokine mRNAs and by repressing the expression of their transcription activator. This study highlights that cellular RNA metabolism, which is controlled by HCMV for immune evasion, can be the target for developing anti-HCMV therapeutics.</P><P>RNA represents a pivotal component of host–pathogen interactions. Human cytomegalovirus (HCMV) infection causes extensive alteration in host RNA metabolism, but the functional relationship between the virus and cellular RNA processing remains largely unknown. Through loss-of-function screening, we show that HCMV requires multiple RNA-processing machineries for efficient viral lytic production. In particular, the cellular RNA-binding protein Roquin, whose expression is actively stimulated by HCMV, plays an essential role in inhibiting the innate immune response. Transcriptome profiling revealed Roquin-dependent global down-regulation of proinflammatory cytokines and antiviral genes in HCMV-infected cells. Furthermore, using cross-linking immunoprecipitation (CLIP)-sequencing (seq), we identified IFN regulatory factor 1 (<I>IRF1</I>), a master transcriptional activator of immune responses, as a Roquin target gene. Roquin reduces IRF1 expression by directly binding to its mRNA, thereby enabling suppression of a variety of antiviral genes. This study demonstrates how HCMV exploits host RNA-binding protein to prevent a cellular antiviral response and offers mechanistic insight into the potential development of CMV therapeutics.</P>