Journal
MOBILE DNA
Volume 13, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13100-022-00268-0
Keywords
LINE-1; MDA5; Retrotransposition; 5 '-UTR; Promoter regulation
Categories
Funding
- National Natural Science Foundation of China [32170146, 32170140, 32100108, 81601363, 81902049]
- China Postdoctoral Science Foundation [2020 M670843]
- Fundamental Research Funds for the Central Universities [2017TD-08]
- Science and Technology Department of Jilin Province [20200201525JC]
- Key Laboratory of Molecular Virology, Jilin Province [20102209]
- Norman Bethune Health Science Centre of Jilin University [2018B18]
- First Hospital of Jilin University [2020-CXQ-02, JDYY102019015, 2020JC03]
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The study found that MDA5 suppresses LINE-1 activity by inhibiting the promoter activity of LINE-1 and reducing the levels of LINE-1 RNA and proteins. The N-terminal 2CARD domain of MDA5 plays a crucial role in inhibiting LINE-1 replication.
Background: 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-Goutieres 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. Results: 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. Conclusion: 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.
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