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

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,...

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Autores principales: Akaki, Kotaro, Ogata, Kosuke, Yamauchi, Yuhei, Iwai, Noriki, Tse, Ka Man, Hia, Fabian, Mochizuki, Atsushi, Ishihama, Yasushi, Mino, Takashi, Takeuchi, Osamu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553338/
https://www.ncbi.nlm.nih.gov/pubmed/34636324
http://dx.doi.org/10.7554/eLife.71966
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author Akaki, Kotaro
Ogata, Kosuke
Yamauchi, Yuhei
Iwai, Noriki
Tse, Ka Man
Hia, Fabian
Mochizuki, Atsushi
Ishihama, Yasushi
Mino, Takashi
Takeuchi, Osamu
author_facet Akaki, Kotaro
Ogata, Kosuke
Yamauchi, Yuhei
Iwai, Noriki
Tse, Ka Man
Hia, Fabian
Mochizuki, Atsushi
Ishihama, Yasushi
Mino, Takashi
Takeuchi, Osamu
author_sort Akaki, Kotaro
collection PubMed
description 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.
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spelling pubmed-85533382021-10-29 IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay Akaki, Kotaro Ogata, Kosuke Yamauchi, Yuhei Iwai, Noriki Tse, Ka Man Hia, Fabian Mochizuki, Atsushi Ishihama, Yasushi Mino, Takashi Takeuchi, Osamu eLife Immunology and Inflammation 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. eLife Sciences Publications, Ltd 2021-10-12 /pmc/articles/PMC8553338/ /pubmed/34636324 http://dx.doi.org/10.7554/eLife.71966 Text en © 2021, Akaki et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Akaki, Kotaro
Ogata, Kosuke
Yamauchi, Yuhei
Iwai, Noriki
Tse, Ka Man
Hia, Fabian
Mochizuki, Atsushi
Ishihama, Yasushi
Mino, Takashi
Takeuchi, Osamu
IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
title IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
title_full IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
title_fullStr IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
title_full_unstemmed IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
title_short IRAK1-dependent Regnase-1-14-3-3 complex formation controls Regnase-1-mediated mRNA decay
title_sort irak1-dependent regnase-1-14-3-3 complex formation controls regnase-1-mediated mrna decay
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553338/
https://www.ncbi.nlm.nih.gov/pubmed/34636324
http://dx.doi.org/10.7554/eLife.71966
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