IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay.
IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay.
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DOI：
10.7554/elife.71966
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发表时间：
2021-10-12
期刊：
影响因子：
7.7
通讯作者：
Takeuchi O
中科院分区：
文献类型：
--
作者：
Akaki K;Ogata K;Yamauchi Y;Iwai N;Tse KM;Hia F;Mochizuki A;Ishihama Y;Mino T;Takeuchi O
Regnase-1是一种核糖核酸内切酶，通过降解哺乳动物中编码细胞因子和炎症介质的mRNA来控制炎症。然而，目前尚不清楚Regnase-1介导的mRNA衰减在白细胞介素（IL）-1β或Toll样受体（TLR）配体刺激的细胞中是如何控制的。通过对Regnase-1相互作用组的分析，我们发现IL-1β或TLR刺激可动态诱导Regnase-1-β-transducin repeat-containing protein（βTRCP）复合物的形成。重要的是，我们还发现了Regnase-1和14-3-3在小鼠和人细胞中的新型相互作用。在IL-1 R/TLR刺激的细胞中，Regnase-1-14-3-3相互作用由IRAK 1通过先前未表征的C末端结构域介导。Regnase-1在S494和S513处的磷酸化对于Regnase-1-14-3-3相互作用至关重要，而已知Regnase-1的一组不同的磷酸化位点是βTRCP识别和蛋白酶体介导的降解所需的。我们发现Regnase-1-14-3-3和Regnase-1-βTRCP相互作用不是顺序事件。相反，14-3-3保护Regnase-1免受β TRCP介导的降解。另一方面，14-3-3通过抑制Regnase-1-mRNA结合来消除Regnase-1介导的mRNA衰减。此外，Regnase-1的核质穿梭被14-3-3相互作用消除。总之，结果表明，14-3-3与Regnase-1的新型炎症诱导的相互作用通过在细胞质中隔离Regnase-1以防止mRNA识别来稳定炎性mRNA。
Regnase-1 is an endoribonuclease crucial for controlling inflammation by degrading mRNAs encoding cytokines and inflammatory mediators in mammals. However, it is unclear how Regnase-1-mediated mRNA decay is controlled in interleukin (IL)-1β- or Toll-like receptor (TLR) ligand-stimulated cells. Here, by analyzing the Regnase-1 interactome, we found that IL-1β or TLR stimulus dynamically induced the formation of Regnase-1-β-transducin repeat-containing protein (βTRCP) complex. Importantly, we also uncovered a novel interaction between Regnase-1 and 14-3-3 in both mouse and human cells. In IL-1R/TLR-stimulated cells, the Regnase-1-14-3-3 interaction is mediated by IRAK1 through a previously uncharacterized C-terminal structural domain. Phosphorylation of Regnase-1 at S494 and S513 is critical for Regnase-1-14-3-3 interaction, while a different set of phosphorylation sites of Regnase-1 is known to be required for the recognition by βTRCP and proteasome-mediated degradation. We found that Regnase-1-14-3-3 and Regnase-1-βTRCP interactions are not sequential events. Rather, 14-3-3 protects Regnase-1 from βTRCP-mediated degradation. On the other hand, 14-3-3 abolishes Regnase-1-mediated mRNA decay by inhibiting Regnase-1-mRNA association. In addition, nuclear-cytoplasmic shuttling of Regnase-1 is abrogated by 14-3-3 interaction. Taken together, the results suggest that a novel inflammation-induced interaction of 14-3-3 with Regnase-1 stabilizes inflammatory mRNAs by sequestering Regnase-1 in the cytoplasm to prevent mRNA recognition.