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Series GSE218957 Query DataSets for GSE218957
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
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.  
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
Contributor(s) Reja R
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Submission date Nov 29, 2022
Last update date Apr 02, 2024
Contact name Rohit Reja
Phone +1-650-467-7615
Organization name Genentech
Street address 1 DNA Way
City South San Francisco
State/province CA
ZIP/Postal code 94080
Country USA
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (4)
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
This SubSeries is part of SuperSeries:
GSE218958 Regulation of IkB kinase family crosstalk by an N4BP1-caspase-8 axis
BioProject PRJNA906452

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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 SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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