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【解放日報】科學家合作揭示環形RNA在天然免疫過程中的重要功能

文章來源:解放日報 黃海華   發布時間:2019-04-26  【字號:     】  

  中科院生物化學與細胞生物學研究所陳玲玲研究組發現,環形RNA(核糖核酸)管理著抗病毒“衛士”——天然免疫因子PKR的活性。在細胞受到病毒感染時,環形RNA會被大規模“清除”,從而釋放PKR參與抗病毒免疫反應;而在PKR過度激活的紅斑狼瘡病人體內,環形RNA含量顯著降低。該研究不僅為環形RNA代謝和功能研究奠定了重要基礎,也為紅斑狼瘡等自身免疫疾病的臨床診斷和治療提供了新思路。相關論文昨天發表于國際權威學術期刊《細胞》。

  生命體中也有“暗物質”

  宇宙中存在著暗物質,生命體中也存在著“暗物質”——非編碼RNA。人類基因組序列中僅1%—2%為蛋白質編碼序列,98%為非編碼序列。已經有越來越多的證據表明,一些重大疾病與非編碼RNA調控失衡相關。2011年以前,人們以為RNA只有線形結構,近年來,隱身于細胞中數以萬計的非編碼環形RNA逐漸浮出水面,但其至今仍有許多未解之謎。

  在之前的研究中,陳玲玲研究組和中國科學院—馬普學會計算生物學伙伴研究所楊力研究組發現環形RNA“生得曲折”——生成速度特別緩慢。他們在近期研究環形RNA的二級結構過程中發現,它們能夠被天然免疫因子PKR識別并結合,PKR活性因此受到抑制,這樣可以避免體內因PKR過度激活引起的免疫反應。而細胞中的核糖核酸酶RNase L則可以讓PKR恢復自由身,這類酶在細胞受病毒刺激下可作用于環形RNA,將其“切割”降解。“90%以上的環形RNA會被降解,算是‘死得其所’吧!”陳玲玲說,環形RNA由于生成速度特別緩慢,不足以回補這些被降解的環形RNA,天然免疫因子PKR因此得以釋放,參與細胞的抗病毒免疫過程。

  環形RNA過少會怎樣

  顯而易見,過多的環形RNA不利于細胞天然免疫應答,如果環形RNA過少會怎樣?研究人員發現,當環形RNA含量顯著降低,天然免疫因子PKR則會被過度激活。“對于這一結果,我們猜想這一異常情況是否會與炎癥性自身免疫疾病相關。”帶著這樣的疑問,陳玲玲開始了與上海交通大學醫學院附屬仁濟醫院上海風濕病研究所所長沈南教授的合作。

  他們檢測紅斑狼瘡病人體內免疫細胞發現,環形RNA含量相對正常人明顯降低,PKR免疫因子一直處于過度激活狀態,從而引發體內免疫應答系統過度“運轉”。科研人員通過技術手段讓環形RNA在病人來源的免疫細胞內數量增多,可以觀察到過度激活“運轉”的PKR及其下游免疫信號通路被顯著“控制”。

  “這一發現對于我們臨床醫生來說,真是激動人心!”沈南連聲贊嘆。紅斑狼瘡會造成患者多個器官受損,致死率在自身免疫病中居高不下。亞洲人的發病率較高,其中女性患者占90%。我國紅斑狼瘡的發病率為1‰,是西方白種人群的8—10倍,發病人群高達數百萬。盡管在10多年前人們已經知道,抗病毒相關的先天免疫反應在病人身上過度被激活,但究竟是如何被激活的一直不清楚,因此缺乏有效的藥物靶點。目前的臨床治療副作用危害極大,已成為病人死亡的主要原因。“先天免疫反應就像是一匹馬,脫韁了就會橫沖直撞,而環形RNA就像是套在馬上的韁繩。這為解決一直以來困擾我們臨床醫生的發病機理問題提供了新的視角。今年以來,國際上已有多個基于RNA治療的藥物完成了三期臨床試驗。盡管這一發現還是個基礎研究工作,但給紅斑狼瘡的新藥開發帶來了希望。”

  中國工程院院士曹雪濤認為,該工作把環形RNA與天然免疫應答調控機制以及紅斑狼瘡發病機制聯系在一起開展研究,為炎癥性自身免疫疾病發病機制及未來的干預治療提出了新的思路與潛在靶點。

  論文的插圖是一盆盛開的銅錢草,藝術化地展現了如銅錢草葉般的環形RNA,借用銅錢草的藥用價值暗示環形RNA具有潛在應用價值。“如果能夠服務人們的健康,我會歡呼雀躍,但免疫應答是一個非常復雜的過程,未來的路還很長。”陳玲玲說,目前的研究還在細胞水平,接下來將會利用小鼠模型做進一步的嘗試。

  (原載于《解放日報》 2019-04-26 06版)




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