GEO series

Regulation of IkB kinase family crosstalk by an N4BP1-caspase-8 axis [RNA-seq NGS3611]

GSE218955 Mus musculus (mouse) RNA-seq (gene expression) 54 samples Submitted 2024/04/01 Platform GPL21103

At a glance

RNA-seq (gene expression) · mouse · 54 samples

What it is: RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism: Mus musculus (mouse)
Samples: 54 samples: 18 conditions, mostly in triplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper: N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammationImmunity · 2024

Summary (written by the submitters)

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.

Read the full summary ↓

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.

Published in

N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation

Gitlin AD, Maltzman A, Kanno Y et al. · Immunity 2024 · PMID 38697117 · doi:10.1016/j.immuni.2024.04.004

This dataset

Open GSE218955 in finder → Find more mouse RNA-seq datasets →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE218955_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA906450 and SRA study SRP410393. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38697117) ↗

Study design

18 conditions, mostly in triplicate

WT BMDMs, untreated, ×3 KO BMDMs, untreated, ×3 WT BMDMs, Pam3 2h, ×3 KO BMDMs, Pam3 2h, ×3 WT BMDMs, Pam3 4h, ×3 KO BMDMs, Pam3 4h, ×3 WT BMDMs, Pam3 6h, ×3 KO BMDMs, Pam3 6h, ×3 +10 more

Supports a between-group comparison across 54 samples.

How we read this: 18 replicated groups read from 54 sample titles; they account for 54 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

GSM6760748 WT BMDMs, untreated, rep 1 WT BMDMs, untreated,
GSM6760749 WT BMDMs, untreated, rep 2 WT BMDMs, untreated,
GSM6760750 WT BMDMs, untreated, rep 3 WT BMDMs, untreated,
GSM6760751 KO BMDMs, untreated, rep 1 KO BMDMs, untreated,
GSM6760752 KO BMDMs, untreated, rep 2 KO BMDMs, untreated,
GSM6760753 KO BMDMs, untreated, rep 3 KO BMDMs, untreated,
GSM6760754 WT BMDMs, Pam3 2h, rep 1 WT BMDMs, Pam3 2h,
GSM6760755 WT BMDMs, Pam3 2h, rep 2 WT BMDMs, Pam3 2h,
GSM6760756 WT BMDMs, Pam3 2h, rep 3 WT BMDMs, Pam3 2h,
GSM6760757 KO BMDMs, Pam3 2h, rep 1 KO BMDMs, Pam3 2h,
GSM6760758 KO BMDMs, Pam3 2h, rep 2 KO BMDMs, Pam3 2h,
GSM6760759 KO BMDMs, Pam3 2h, rep 3 KO BMDMs, Pam3 2h,
GSM6760760 WT BMDMs, Pam3 4h, rep 1 WT BMDMs, Pam3 4h,
GSM6760761 WT BMDMs, Pam3 4h, rep 2 WT BMDMs, Pam3 4h,
GSM6760762 WT BMDMs, Pam3 4h, rep 3 WT BMDMs, Pam3 4h,
GSM6760763 KO BMDMs, Pam3 4h, rep 1 KO BMDMs, Pam3 4h,
GSM6760764 KO BMDMs, Pam3 4h, rep 2 KO BMDMs, Pam3 4h,
GSM6760765 KO BMDMs, Pam3 4h, rep 3 KO BMDMs, Pam3 4h,
GSM6760766 WT BMDMs, Pam3 6h, rep 1 WT BMDMs, Pam3 6h,
GSM6760767 WT BMDMs, Pam3 6h, rep 2 WT BMDMs, Pam3 6h,
GSM6760768 WT BMDMs, Pam3 6h, rep 3 WT BMDMs, Pam3 6h,
GSM6760769 KO BMDMs, Pam3 6h, rep 1 KO BMDMs, Pam3 6h,
GSM6760770 KO BMDMs, Pam3 6h, rep 2 KO BMDMs, Pam3 6h,
GSM6760771 KO BMDMs, Pam3 6h, rep 3 KO BMDMs, Pam3 6h,
GSM6760772 WT BMDMs, Pam3 8h, rep 1 WT BMDMs, Pam3 8h,
GSM6760773 WT BMDMs, Pam3 8h, rep 2 WT BMDMs, Pam3 8h,
GSM6760774 WT BMDMs, Pam3 8h, rep 3 WT BMDMs, Pam3 8h,
GSM6760775 KO BMDMs, Pam3 8h, rep 1 KO BMDMs, Pam3 8h,
GSM6760776 KO BMDMs, Pam3 8h, rep 2 KO BMDMs, Pam3 8h,
GSM6760777 KO BMDMs, Pam3 8h, rep 3 KO BMDMs, Pam3 8h,
GSM6760778 WT BMDMs, R837 2h, rep 1 WT BMDMs, R837 2h,
GSM6760779 WT BMDMs, R837 2h, rep 2 WT BMDMs, R837 2h,
GSM6760780 WT BMDMs, R837 2h, rep 3 WT BMDMs, R837 2h,
GSM6760781 KO BMDMs, R837 2h, rep 1 KO BMDMs, R837 2h,
GSM6760782 KO BMDMs, R837 2h, rep 2 KO BMDMs, R837 2h,
GSM6760783 KO BMDMs, R837 2h, rep 3 KO BMDMs, R837 2h,
GSM6760784 WT BMDMs, R837 4h, rep 1 WT BMDMs, R837 4h,
GSM6760785 WT BMDMs, R837 4h, rep 2 WT BMDMs, R837 4h,
GSM6760786 WT BMDMs, R837 4h, rep 3 WT BMDMs, R837 4h,
GSM6760787 KO BMDMs, R837 4h, rep 1 KO BMDMs, R837 4h,

+ 14 more — browse all 54 samples with per-sample file links →

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Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.