RT Journal Article
SR Electronic
T1 IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.15.452458
DO 10.1101/2021.07.15.452458
A1 Kotaro Akaki
A1 Kosuke Ogata
A1 Yuhei Yamauchi
A1 Noriki Iwai
A1 Ka Man Tse
A1 Fabian Hia
A1 Atsushi Mochizuki
A1 Yasushi Ishihama
A1 Takashi Mino
A1 Osamu Takeuchi
YR 2021
UL http://biorxiv.org/content/early/2021/07/15/2021.07.15.452458.abstract
AB 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. Strikingly, both interactions occur in a mutually exclusive manner, underscoring the importance of modulating Regnase-1’s activity. Additionally, we show that 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 are known to be required for the recognition by βTRCP and proteasome-mediated degradation. 14-3-3 stabilizes Regnase-1 but abolishes its activity by inhibiting Regnase-1-mRNA association. Furthermore, 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.Competing Interest StatementThe authors have declared no competing interest.