Prof. Xuetao Cao’s Group Discovered the New Epigenetic Regulatory Mechanism for Antiviral Innate Immunity
Source：Qingliang Zheng
2017-10-13
On August 29, 2017, Prof. Xuetao Cao (Peking Union Medical College, Chinese Academy of Medical Sciences) and his group published a research article in Nature Immunology about the identification of RNA helicase DDX46as a critical modulator of antiviral innate immunity (Zheng, Q., Hou, J., Zhou, Y., Li, Z. & Cao, X. The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus. Nat Immunol 18, 1094-1103 (2017).).
Type I interferons have vital roles in the innate defense against viralinfection. Interferon productionduring viral infection is tightly controlled to prevent harmful immunopathology after elimination of the invading virus, However, molecular regulation of the production of type I interferonhas focused mainly on cytosolic regulators of innate signaling, whether nuclear factors also have important roles in this process islargely unknown. Members of the DEAD-box (DDX) family of helicases are the largest family of helicases that are important inthe antiviral innate immune response, most members of the DDX family are located inthe nucleus and control nearly every aspect of RNA metabolism, therefore, it is possible that these nuclear helicases regulate antiviral innate immune responses through RNA modification. N6-methyladenosine (m6A) is the most prevalent internal modification on eukaryotic mRNA. However, whether the m6A modification participates in the regulation of antiviral innate immunity, especiallyin the regulating the production of type I interferon, is unknown.
In this paper, the authors revealed a new function of nuclear DDX member DDX46 which inhibited the production of type I interferon after viral infection. The authors performed the iCLIP-seq and found that DDX46bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. Further investigation showed that, after viral infection, DDX46 recruited ALKBH5, an ‘eraser’ of the RNA modification N6-methyladenosine(m6A), via DDX46’s DEAD helicase domain to demethylate those m6A-modified antiviral transcripts. It consequently enforced theirretention in the nucleus and therefore prevented their translation and inhibited interferon production. Importantly, they also found that DDX46 suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in thenucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation.
Dr. Qingliang Zheng and Prof. Jin Hou are the co-first authors of this paper. Prof. Xuetao Cao is the corresponding author. This paper might add insight into the action of the m6A RNA modification in regulating innate response and inflammation and might provide potential targets for controlling infection and inflammatory disease. This work was supported by grants from the National Key Basic Research Program of China, the National Natural Science Foundation of China and the CAMS Innovation Fund for Medical Sciences.
Type I interferons have vital roles in the innate defense against viralinfection. Interferon productionduring viral infection is tightly controlled to prevent harmful immunopathology after elimination of the invading virus, However, molecular regulation of the production of type I interferonhas focused mainly on cytosolic regulators of innate signaling, whether nuclear factors also have important roles in this process islargely unknown. Members of the DEAD-box (DDX) family of helicases are the largest family of helicases that are important inthe antiviral innate immune response, most members of the DDX family are located inthe nucleus and control nearly every aspect of RNA metabolism, therefore, it is possible that these nuclear helicases regulate antiviral innate immune responses through RNA modification. N6-methyladenosine (m6A) is the most prevalent internal modification on eukaryotic mRNA. However, whether the m6A modification participates in the regulation of antiviral innate immunity, especiallyin the regulating the production of type I interferon, is unknown.
In this paper, the authors revealed a new function of nuclear DDX member DDX46 which inhibited the production of type I interferon after viral infection. The authors performed the iCLIP-seq and found that DDX46bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. Further investigation showed that, after viral infection, DDX46 recruited ALKBH5, an ‘eraser’ of the RNA modification N6-methyladenosine(m6A), via DDX46’s DEAD helicase domain to demethylate those m6A-modified antiviral transcripts. It consequently enforced theirretention in the nucleus and therefore prevented their translation and inhibited interferon production. Importantly, they also found that DDX46 suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in thenucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation.
Dr. Qingliang Zheng and Prof. Jin Hou are the co-first authors of this paper. Prof. Xuetao Cao is the corresponding author. This paper might add insight into the action of the m6A RNA modification in regulating innate response and inflammation and might provide potential targets for controlling infection and inflammatory disease. This work was supported by grants from the National Key Basic Research Program of China, the National Natural Science Foundation of China and the CAMS Innovation Fund for Medical Sciences.
