IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay

eLife

Osamu Takeuchi¹  Takashi Mino¹  Noriki Iwai¹  Ka Man Tse¹  Fabian Hia¹  Kotaro Akaki²  Kosuke Ogata³  Yasushi Ishihama³  Yuhei Yamauchi⁴  Atsushi Mochizuki⁴ 

[1] Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Graduate School of Biostudies, Kyoto University, Kyoto, Japan;Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;Laboratory of Mathematical Biology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan;

关键词: post-transcriptional regulation;    inflammation;    14-3-3;    phosphorylation;    RNase;    interactome;    Human;    Mouse;   

DOI  :  10.7554/eLife.71966

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY