RNA sensor MDA5 suppresses LINE-1 retrotransposition by regulating the promoter activity of LINE-1 5'-UTR.
RNA sensor MDA5 suppresses LINE-1 retrotransposition by regulating the promoter activity of LINE-1 5'-UTR.
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RNA 传感器 MDA5 通过调节 LINE-1 5-UTR 的启动子活性来抑制 LINE-1 逆转录转座
DOI：
10.1186/s13100-022-00268-0
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发表时间：
2022-04-12
期刊：
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
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作者：
1型长散布元件，或LINE-1，是唯一在人类细胞中自主复制的逆转录元件。LINE-1的逆转录转座过程可以触发先天免疫系统的激活，并已被提出在几种自身免疫性疾病的发展中发挥作用，包括Aicardi-Goutières综合征（AGS）。相比之下，所有已知的AGS相关蛋白，除了MDA 5，已被报道影响LINE-1的活性。因此，MDA 5也可能作为LINE-1抑制剂发挥作用。在基于荧光素酶的LINE-1逆转录转座试验中发现MDA 5有效抑制LINE-1活性。虽然MDA 5是一种能够激活先天免疫系统的内源性RNA传感器，但干扰素（IFN）表达的增加仅部分有助于MDA 5介导的LINE-1抑制。相反，MDA 5有效地调节LINE-1 5′-UTR的启动子活性，如通过瞬时表达myc-taged MDA 5或敲低内源性MDA 5表达所证实的。因此，MDA 5有效地减少了LINE-1 RNA的产生以及随后LINE-1 ORF 1 p和ORF 2 p的表达。有趣的是，尽管MDA 5是一种多结构域蛋白，但仅N-末端2CARD结构域就足以与LINE-1 5′-UTR相互作用并抑制LINE-1启动子活性。我们的数据表明，MDA 5作为启动子调节剂发挥作用;它直接结合LINE-1 5′-UTR并抑制其启动子活性。因此，MDA 5降低LINE-1 RNA和蛋白水平，并最终抑制LINE-1逆转录转座。相比之下，MDA 5诱导的IFN表达在MDA 5介导的LINE-1抑制中仅起轻微作用。此外，发现N-末端2CARD结构域在抑制LINE-1复制时是MDA 5的功能区域。因此，我们的数据表明，除了作为先天免疫系统的启动子，MDA 5也是针对LINE-1活性的效应子，可能通过抑制LINE-1诱导的先天免疫激活形成反馈环。在线版本包含补充材料，可通过10.1186/s13100-022-00268-0获得。
Type 1 long interspersed elements, or LINE-1, are the only retroelements that replicate autonomously in human cells. The retrotransposition process of LINE-1 can trigger the activation of the innate immune system and has been proposed to play a role in the development of several autoimmune diseases, including Aicardi-Goutières syndrome (AGS). In contrast, all known AGS-associated proteins, except MDA5, have been reported to affect LINE-1 activity. Thus, MDA5 is likely to also function as a LINE-1 suppressor. MDA5 was found to potently suppress LINE-1 activity in a reporter-based LINE-1 retrotransposition assay. Although MDA5 is an endogenous RNA sensor able to activate the innate immune system, increased interferon (IFN) expression only contributed in part to MDA5-mediated LINE-1 suppression. Instead, MDA5 potently regulated the promoter activity of LINE-1 5′-UTR, as confirmed by transiently expressed myc-tagged MDA5 or knockdown of endogenous MDA5 expression. Consequently, MDA5 effectively reduced the generation of LINE-1 RNA and the subsequent expression of LINE-1 ORF1p and ORF2p. Interestingly, despite MDA5 being a multi-domain protein, the N-terminal 2CARD domain alone is sufficient to interact with LINE-1 5′-UTR and inhibit LINE-1 promoter activity. Our data reveal that MDA5 functions as a promoter regulator; it directly binds to the LINE-1 5′-UTR and suppresses its promoter activity. Consequently, MDA5 reduces LINE-1 RNA and protein levels, and ultimately inhibits LINE-1 retrotransposition. In contrast, MDA5-induced IFN expression only plays a mild role in MDA5-mediated LINE-1 suppression. In addition, the N-terminal 2CARD domain was found to be a functional region for MDA5 upon inhibition of LINE-1 replication. Thus, our data suggest that besides being an initiator of the innate immune system, MDA5 is also an effector against LINE-1 activity, potentially forming a feedback loop by suppressing LINE-1-induced innate immune activation. The online version contains supplementary material available at 10.1186/s13100-022-00268-0.
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DOI：
10.1126/science.aac7442
发表时间：
2015-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hung T;Pratt GA;Sundararaman B;Townsend MJ;Chaivorapol C;Bhangale T;Graham RR;Ortmann W;Criswell LA;Yeo GW;Behrens TW
通讯作者：
Behrens TW
影响因子：
3.7
作者：
Baehr, Ariane;Singer, Anna;Muenk, Carsten
通讯作者：
Muenk, Carsten
影响因子：
4.9
作者：
Hancks DC;Kazazian HH Jr
通讯作者：
Kazazian HH Jr
影响因子：
14.9
作者：
Choi J;Hwang SY;Ahn K
通讯作者：
Ahn K
DOI：
10.1084/jem.20160592
发表时间：
2017-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lang X;Tang T;Jin T;Ding C;Zhou R;Jiang W
通讯作者：
Jiang W