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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Apr 01, 2024 |
| Title |
Regulation of IkB kinase family crosstalk by an N4BP1-caspase-8 axis [RNA-seq NGS3611] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The cell death protease caspase-8 plays an essential role in controlling inflammation, as severe immunodeficiency results from its loss. We previously found that caspase-8 promotes inflammatory responses by cleaving NEDD4-binding protein 1 (N4BP1), a suppressor of cytokine production, but the underlying mechanisms remained unclear. Here we find that N4BP1 curtails the duration, rather than initial induction, of proinflammatory signaling through a mechanism involving noncanonical IKK (ncIKK)-mediated inhibition of the canonical IkB kinase (IKK) complex, a crosstalk event among the IKK family facilitated by N4BP1. Accordingly, co-deletion of the ncIKKs or their adaptor protein TANK largely phenocopied deletion of N4BP1, augmenting cytokine responses by macrophages upon engagement of TRIF-independent toll-like receptors (TLR) 1/2, TLR7, or TLR9. Like N4BP1, TANK was largely prevented from inhibiting the TRIF-dependent TLR4 response due to caspase-8. Biochemically, N4BP1 binds both the canonical and noncanonical IKK complexes, in a manner promoted by linear and/or K63-linked polyubiquitin chain binding by N4BP1 and independent of its RNAse activity. Consistent with this, a knock-in mutant of N4BP1 with diminished ubiquitin chain-binding capacity led to increased proinflammatory cytokine responses. These findings thereby unveil a mechanism of late-phase inflammatory gene control, whereby N4BP1 prevents persistent IKK activity through ncIKK-mediated inhibition. This molecular crosstalk among caspase-8, N4BP1, and the IKKs and ncIKKs may have implications for our understanding of genetic immune diseases caused by mutations in caspase-8 or TBK1 and suggest a novel ‘guarding’ mechanism against pathogens that attempt to subvert the ncIKKs.
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| Overall design |
Time course of N4bp1 knockout or wildtype mouse Bone Marrow Derived Macrophages (BMDMs) treated with Pam3csk4 or R837
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| Contributor(s) |
Reja R |
| Citation(s) |
38697117 |
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| Submission date |
Nov 29, 2022 |
| Last update date |
Aug 13, 2024 |
| Contact name |
Rohit Reja |
| E-mail(s) |
rejar@gene.com
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| Phone |
+1-650-467-7615
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| Organization name |
Genentech
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| Street address |
1 DNA Way
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (54)
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| GSM6760751 |
KO BMDMs, untreated, rep 1 |
| GSM6760752 |
KO BMDMs, untreated, rep 2 |
| GSM6760753 |
KO BMDMs, untreated, rep 3 |
| GSM6760754 |
WT BMDMs, Pam3 2h, rep 1 |
| GSM6760755 |
WT BMDMs, Pam3 2h, rep 2 |
| GSM6760756 |
WT BMDMs, Pam3 2h, rep 3 |
| GSM6760757 |
KO BMDMs, Pam3 2h, rep 1 |
| GSM6760758 |
KO BMDMs, Pam3 2h, rep 2 |
| GSM6760759 |
KO BMDMs, Pam3 2h, rep 3 |
| GSM6760760 |
WT BMDMs, Pam3 4h, rep 1 |
| GSM6760761 |
WT BMDMs, Pam3 4h, rep 2 |
| GSM6760762 |
WT BMDMs, Pam3 4h, rep 3 |
| GSM6760763 |
KO BMDMs, Pam3 4h, rep 1 |
| GSM6760764 |
KO BMDMs, Pam3 4h, rep 2 |
| GSM6760765 |
KO BMDMs, Pam3 4h, rep 3 |
| GSM6760766 |
WT BMDMs, Pam3 6h, rep 1 |
| GSM6760767 |
WT BMDMs, Pam3 6h, rep 2 |
| GSM6760768 |
WT BMDMs, Pam3 6h, rep 3 |
| GSM6760769 |
KO BMDMs, Pam3 6h, rep 1 |
| GSM6760770 |
KO BMDMs, Pam3 6h, rep 2 |
| GSM6760771 |
KO BMDMs, Pam3 6h, rep 3 |
| GSM6760772 |
WT BMDMs, Pam3 8h, rep 1 |
| GSM6760773 |
WT BMDMs, Pam3 8h, rep 2 |
| GSM6760774 |
WT BMDMs, Pam3 8h, rep 3 |
| GSM6760775 |
KO BMDMs, Pam3 8h, rep 1 |
| GSM6760776 |
KO BMDMs, Pam3 8h, rep 2 |
| GSM6760777 |
KO BMDMs, Pam3 8h, rep 3 |
| GSM6760778 |
WT BMDMs, R837 2h, rep 1 |
| GSM6760779 |
WT BMDMs, R837 2h, rep 2 |
| GSM6760780 |
WT BMDMs, R837 2h, rep 3 |
| GSM6760781 |
KO BMDMs, R837 2h, rep 1 |
| GSM6760782 |
KO BMDMs, R837 2h, rep 2 |
| GSM6760783 |
KO BMDMs, R837 2h, rep 3 |
| GSM6760784 |
WT BMDMs, R837 4h, rep 1 |
| GSM6760785 |
WT BMDMs, R837 4h, rep 2 |
| GSM6760786 |
WT BMDMs, R837 4h, rep 3 |
| GSM6760787 |
KO BMDMs, R837 4h, rep 1 |
| GSM6760788 |
KO BMDMs, R837 4h, rep 2 |
| GSM6760789 |
KO BMDMs, R837 4h, rep 3 |
| GSM6760790 |
WT BMDMs, R837 6h, rep 1 |
| GSM6760791 |
WT BMDMs, R837 6h, rep 2 |
| GSM6760792 |
WT BMDMs, R837 6h, rep 3 |
| GSM6760793 |
KO BMDMs, R837 6h, rep 1 |
| GSM6760794 |
KO BMDMs, R837 6h, rep 2 |
| GSM6760795 |
KO BMDMs, R837 6h, rep 3 |
| GSM6760796 |
WT BMDMs, R837 8h, rep 1 |
| GSM6760797 |
WT BMDMs, R837 8h, rep 2 |
| GSM6760798 |
WT BMDMs, R837 8h, rep 3 |
| GSM6760799 |
KO BMDMs, R837 8h, rep 1 |
| GSM6760800 |
KO BMDMs, R837 8h, rep 2 |
| GSM6760801 |
KO BMDMs, R837 8h, rep 3 |
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| This SubSeries is part of SuperSeries: |
| GSE218958 |
Regulation of IkB kinase family crosstalk by an N4BP1-caspase-8 axis |
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| Relations |
| BioProject |
PRJNA906450 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE218955_RAW.tar |
24.7 Mb |
(http)(custom) |
TAR (of TAB) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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