| First Author | Akaki K | Year | 2021 |
| Journal | Elife | Volume | 10 |
| PubMed ID | 34636324 | Mgi Jnum | J:316931 |
| Mgi Id | MGI:6788588 | Doi | 10.7554/eLife.71966 |
| Citation | Akaki K, et al. (2021) IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay. Elife 10:e71966 |
| abstractText | 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)-1beta- or Toll-like receptor (TLR) ligand-stimulated cells. Here, by analyzing the Regnase-1 interactome, we found that IL-1beta or TLR stimulus dynamically induced the formation of Regnase-1-beta-transducin repeat-containing protein (betaTRCP) 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 betaTRCP and proteasome-mediated degradation. We found that Regnase-1-14-3-3 and Regnase-1-betaTRCP interactions are not sequential events. Rather, 14-3-3 protects Regnase-1 from betaTRCP-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. |
