Decision letter: IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay [peer_review]

Georg Stoecklin, Nahum Sonenberg, Carla V Rothlin
2021 unpublished
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)-1b-or Toll-like receptor (TLR) ligand-stimulated cells. Here, by analyzing the Regnase-1 interactome, we found that IL-1b or TLR stimulus dynamically induced the formation of Regnase-1-b-transducin repeat-containing protein (bTRCP) complex. Importantly, we also
more » ... 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 bTRCP and proteasome-mediated degradation. We found that Regnase-1-14-3-3 and Regnase-1-b TRCP interactions are not sequential events. Rather, 14-3-3 protects Regnase-1 from bTRCPmediated 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 inflammationinduced interaction of 14-3-3 with Regnase-1 stabilizes inflammatory mRNAs by sequestering Regnase-1 in the cytoplasm to prevent mRNA recognition.
doi:10.7554/elife.71966.sa1 fatcat:x73b6iqmafd5relsmlitcfwou4