Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
Upstream ORFs Prevent MAVS Spontaneous Aggregation and Regulate Innate Immune Homeostasis
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上游 ORF 防止 MAVS 自发聚集并调节先天免疫稳态
DOI：
10.1016/j.isci.2020.101059
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发表时间：
2020-04
期刊：
影响因子：
5.8
通讯作者：
Nan Qi
中科院分区：
文献类型：
--
作者：
Yuheng Shi;Jing Wu;Tiansheng Zhong;Wenting Zhu;Guolan She;Hao Tang;Wei Du;Bang-Ce Ye;Nan Qi
MAVS的单体到细丝的转变对于RIG-I/MDA 5介导的抗病毒信号传导是必需的。在静止细胞中，单体MAVS处于严格的调节下以防止其自发聚集，这将导致干扰素（IFN-α/β）产生失调和自身免疫性疾病，如系统性红斑狼疮。然而，MAVS防止自发聚集的详细机制在很大程度上仍不清楚。在这里，我们表明，上游开放阅读框架（uORF）内的MAVS转录发挥转录后调节，防止MAVS自发聚集和自动激活。从机制上讲，我们证明了uORF是启动下游ORF密码子的泄漏核糖体扫描的精确作用元件，从而抑制全长MAVS翻译。我们进一步发现，从uORF剥夺的转录本产生的内源性MAVS自发聚集，触发Nix介导的受损线粒体和聚集的MAVS的线粒体吞噬清除。我们的研究结果揭示了uORF介导的MAVS的数量和质量控制，防止异常蛋白质聚集和维持先天免疫稳态。
The monomer-to-filament transition of MAVS is essential for the RIG-I/MDA5-mediated antiviral signaling. In quiescent cells, monomeric MAVS is under strict regulation for preventing its spontaneous aggregation, which would result in dysregulated interferon (IFN-α/β) production and autoimmune diseases like systemic lupus erythematosus. However, the detailed mechanism by which MAVS is kept from spontaneous aggregation remains largely unclear. Here, we show that upstream open reading frames (uORFs) within theMAVStranscripts exert a post-transcriptional regulation for preventing MAVS spontaneous aggregation and auto-activation. Mechanistically, we demonstrate that uORFs arecis-acting elements initiating leaky ribosome scanning of the downstream ORF codons, thereby repressing the full-length MAVS translation. We further uncover that endogenous MAVS generated from the uORF-deprived transcript spontaneously aggregates, triggering the Nix-mediated mitophagic clearance of damaged mitochondria and aggregated MAVS. Our findings reveal the uORF-mediated quantity and quality control of MAVS, which prevents aberrant protein aggregation and maintains innate immune homeostasis.
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DOI：
10.1083/jcb.137.4.825
发表时间：
1997-05-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Agarraberes FA;Terlecky SR;Dice JF
通讯作者：
Dice JF
影响因子：
30.3
作者：
Randow F;Youle RJ
通讯作者：
Youle RJ
影响因子：
64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R
影响因子：
30.8
作者：
Mendell, JT;Sharifi, NA;Dietz, HC
通讯作者：
Dietz, HC
影响因子：
64.5
作者：
Zandi, E;Rothwarf, DM;Karin, M
通讯作者：
Karin, M