科研成果: “The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus”

发布时间:2017-09-04


导读: 本重点实验室免疫学系暨中国医学科学院免疫治疗研究中心曹雪涛院士课题组和第二军医大学医学免疫学国家重点实验室的侯晋教授联合攻关,证实RNA解旋酶DDX46能使抗病毒转录子的mRNA发生去m6A甲基化修饰从而形成核滞留,进而参与抑制抗病毒天然免疫。这一重要的免疫表观调控新机制发表在8月29日的《自然免疫学》(Nature Immunology)杂志上,文章题目“The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus”。文章链接:https://www.nature.com/ni/journal/vaop/ncurrent/full/ni.3830.html。


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      中国医学科学院基础医学研究所,“医学分子生物学国家重点实验室”的曹雪涛院士研究团队和第二军医大学医学免疫学国家重点实验室的侯晋教授联合攻关,研究发现在病毒感染小鼠腹腔巨噬细胞后,DDX46能显著抑制I型干扰素的表达,iCLIP-seq发现DDX46能结合到MAVS,TRAF3和TRAF6的CCGGUU保守基序上。当病毒感染后,DDX46与m6A去甲基化酶ALKBH5之间的结合显著增强,使得与DDX46结合的抗病毒转录子发生m6A去甲基化修饰而形成核滞留,下调抗病毒转录子的蛋白表达从而负向调控I型干扰素的表达。此外,在DDX46+/-小鼠的体内实验中也进一步验证了DDX46能抑制抗病毒天然免疫应答。

     【摘要】:DEAD-box (DDX) helicases are vital for the recognition of RNA and metabolism and are critical for the initiation of antiviral innate immunity. Modification of RNA is involved in many biological processes; however, its role in antiviral innate immunity has remained unclear. Here we found that nuclear DDX member DDX46 inhibited the production of type I interferons after viral infection. DDX46 bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. 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 their retention in the nucleus and therefore prevented their translation and inhibited interferon production. DDX46 also suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in the nucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation. 

    本文通讯作者为曹雪涛院士,第一作者郑青亮曾经做为曹雪涛院士的博士后,在其课题组做研究工作。该研究工作得到了973计划、国家自然科学基金、中国医学科学院医学与健康科技创新工程等项目的资助。


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