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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 [scRNA-seq] |
| 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 |
Single cell transcriptome on wildtype and N4bp1 mouse bone marrow derived macrophages (BMDMs) that were co-cultured with GFP expressing BMDMs, with and without TLR7 treatment
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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) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (4)
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| GSM6760838 |
50% WT GFP+ BMDMs and 50% WT BMDMs unstimulated |
| GSM6760839 |
50% WT GFP+ BMDMs and 50% N4bp1 KO BMDMs unstimulated |
| GSM6760840 |
50% WT GFP+ BMDMs and 50% WT BMDMs + TLR7 stimulation |
| GSM6760841 |
50% WT GFP+ BMDMs and 50% N4bp1 KO BMDMs + TLR7 stimulation |
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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 |
PRJNA906452 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE218957_RAW.tar |
699.8 Mb |
(http)(custom) |
TAR (of MTX) |
| GSE218957_barcodes.tsv.gz |
18.5 Mb |
(ftp)(http) |
TSV |
| GSE218957_features.tsv.gz |
423.0 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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