IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
- Kyoto University, Japan
Abstract
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.
Data availability
Mass spectrometry data (PXD026561) is available athttps://repository.jpostdb.org/entry/JPST001201RNA sequencing data (GSE180028) is available athttp://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE180028j
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (19H03488)
- Osamu Takeuchi
Japan Agency for Medical Research and Development (JP20gm4010002)
- Osamu Takeuchi
Japan Society for the Promotion of Science (19H03488)
- Takashi Mino
Japan Society for the Promotion of Science (Core-to-Core Program)
- Osamu Takeuchi
Japan Society for the Promotion of Science (221S0002)
- Takashi Mino
Japan Society for the Promotion of Science (16H06279)
- Takashi Mino
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were conducted in compliance with the guidelines of the Kyoto University animal experimentation committee. (Approval number: MedKyo21057)
Copyright
© 2021, Akaki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
eLife 10:e71966.
https://doi.org/10.7554/eLife.71966
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