title: A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKε.
abstract: Type I interferon (IFN) signaling is the principal response mediating antiviral innate immunity. IFN transcription is dependent upon the activation of transcription factors IRF3/IRF7 and NF-κB. Many viral proteins have been shown as being capable of interfering with IFN signaling to facilitate evasion from the host innate immune response. Here, we report that a viral miRNA, miR-K12-11, encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) is critical for the modulation of IFN signaling and acts through targeting I-kappa-B kinase epsilon (IKKɛ). Ectopic expression of miR-K12-11 resulted in decreased IKKɛ expression, while inhibition of miR-K12-11 was found to restore IKKɛ expression in KSHV-infected cells. Importantly, expression of miR-K12-11 attenuated IFN signaling by decreasing IKKɛ-mediated IRF3/IRF7 phosphorylation and by inhibiting the activation of IKKɛ-dependent IFN stimulating genes (ISGs), allowing miR-K12-11 suppression of antiviral immunity. Our data suggest that IKKɛ targeting by miR-K12-11 is an important strategy utilized by KSHV to modulate IFN signaling during the KSHV lifecycle, especially in latency. We also demonstrated that IKKɛ was able to enhance KSHV reactivation synergistically with the treatment of 12-O-tetradecanoylphorbol 13-acetate. Moreover, inhibition of miR-K12-11 enhanced KSHV reactivation induced by vesicular stomatitis virus infection. Taken together, our findings also suggest that miR-K12-11 can contribute to maintenance of KSHV latency by targeting IKKɛ.
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Deguang
authors.initials: D
authors.lastname: Liang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Lin
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: He
authors.forename: Qinglan
authors.initials: Q
authors.lastname: Zhao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Deng
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D012514:Sarcoma, Kaposi / Q000821:virology; D015398:Signal Transduction; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D007372:Interferons; D051550:I-kappa B Kinase