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| Status |
Public on Oct 12, 2021 |
| Title |
Transcriptome analysis of LPS stimulated PECs (WT and Zc3h12a S513A) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Transcriptome analysis of thioglycollate-elicited PECs derived from WT and Regnase-1 (Zc3h12a) S513A knock-in mice. Cells were stimulated with LPS for 0, 4, or 8 hours.
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| Contributor(s) |
Akaki K, Hia F, Kakiuchi N, Ogawa S, Takeuchi O |
| Citation(s) |
34636324 |
| |
| Submission date |
Jul 13, 2021 |
| Last update date |
Jan 11, 2022 |
| Contact name |
Kotaro Akaki |
| E-mail(s) |
akakikotaro@gmail.com
|
| Organization name |
Kyoto University
|
| Department |
Department of Medical Chemistry
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| Street address |
Sakyo-ku, Yoshidakonoecho
|
| City |
Kyoto |
| ZIP/Postal code |
606-8501 |
| Country |
Japan |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA746300 |
| SRA |
SRP328189 |
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