Integration of Innate 1 Immune Signaling by Caspase-8-Mediated Cleavage of N4BP1 (NGS3269 RNA-seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA662778 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12621843.fastq.gz | Fastqsanger.gz | |||
| SRR12621844.fastq.gz | Fastqsanger.gz | |||
| SRR12621845.fastq.gz | Fastqsanger.gz | |||
| SRR12621846.fastq.gz | Fastqsanger.gz | |||
| SRR12621847.fastq.gz | Fastqsanger.gz |
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Project description:Integration of Innate Immune Signaling by 2 Caspase-8-Mediated Cleavage of N4BP1
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Project description:Human mutations in the death receptor Fas or its ligand FasL cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD â which mediate cell death downstream of Fas/FasL â cause severe immunodeficiency in addition to ALPS. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice significantly increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Illustrating the importance of this function of TNF in vivo, TNF blockade increased the mortality of mice infected with Streptococcus Pneumoniae, but did not do so when infected mice lacked N4BP1. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by Caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
2020-09-10 | GSE157786 | GEO
Project description:Human mutations in the death receptor Fas or its ligand FasL cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD â which mediate cell death downstream of Fas/FasL â cause severe immunodeficiency in addition to ALPS. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice significantly increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Illustrating the importance of this function of TNF in vivo, TNF blockade increased the mortality of mice infected with Streptococcus Pneumoniae, but did not do so when infected mice lacked N4BP1. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by Caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
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Project description:Integration of Innate 1 Immune Signaling by Caspase-8-Mediated Cleavage of N4BP1
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Project description:Integration of Innate 1 Immune Signaling by Caspase-8-Mediated Cleavage of N4BP1 (NGS2979 RNA-seq)
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Project description: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.
2024-04-01 | GSE218954 | GEO
Project description: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.
2024-04-01 | GSE218957 | GEO
Project description: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.
2024-04-01 | GSE218956 | GEO
Project description: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.
2024-04-01 | GSE218955 | GEO
Project description: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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