Modular architecture of the STING C-terminal tail allows interferon and NF-κB signaling adaptation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA527269 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8733751.fastq.gz | Fastqsanger.gz | |||
| SRR8733752.fastq.gz | Fastqsanger.gz | |||
| SRR8733753.fastq.gz | Fastqsanger.gz | |||
| SRR8733754.fastq.gz | Fastqsanger.gz | |||
| SRR8733755.fastq.gz | Fastqsanger.gz |
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Project description:Stimulator of Interferon Genes (STING) is a key regulator of type I interferon and pro-inflammatory responses during infection, cellular stress, and cancer. Here we reveal a mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription, and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal structure that explains how this CTT sequence recruits TRAF6 as a new binding partner, and demonstrate that the minimal motif is sufficient to reprogram human STING and immune activation in macrophage cells. Together, our results define the STING CTT as a linear signaling hub that can acquire modular motifs to readily adapt downstream immunity.
2019-06-10 | GSE128363 | GEO
Project description:Stimulator of interferon genes (STING) is a key regulator of type I interferon and pro-inflammatory responses during infection, cellular stress, and cancer. Here, we reveal a mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal structure that explains how this CTT sequence recruits TRAF6 as a new binding partner and demonstrate that the minimal motif is sufficient to reprogram human STING and immune activation in macrophage cells. Together, our results define the STING CTT as a linear signaling hub that can acquire modular motifs to readily adapt downstream immunity.
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Project description:A series of yeast carrying K->R mutations in the histone H4 N-terminal tail were profiled by gene expression array in mid-log phase.
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Project description:A series of yeast carrying K->R mutations in the histone H4 N-terminal tail were profiled by gene expression array in mid-log phase. Keywords: repeat sample
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Project description:This SuperSeries is composed of the following subset Series: GSE24770: Heterochronic Evolution Reveals Modular Timing Changes in Budding Yeast Transcriptomes (Mutation Accumulation Lines) GSE24771: Heterochronic Evolution Reveals Modular Timing Changes in Budding Yeast Transcriptomes (Natural Strain Timecourse) Refer to individual Series
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Project description:We employ the well-studied fission yeast centromere to investigate the function of the CENP-A (Cnp1) N-tail. We show that alteration of the N-tail did not affect Cnp1 loading at centromeres, outer kinetochore formation, or spindle checkpoint signaling, but nevertheless elevated chromosome loss. N-Tail mutants exhibited synthetic lethality with an altered centromeric DNA sequence, with rare survivors harboring chromosomal fusions in which the altered centromere was epigenetically inactivated. Elevated centromere inactivation was also observed for N-tail mutants with unaltered centromeric DNA sequences. N-tail mutants specifically reduced localization of the CCAN proteins Cnp20/CENP-T and Mis6/CENP-I, but not Cnp3/CENP-C. Overexpression of Cnp20/CENP-T suppressed defects in an N-tail mutant, suggesting a causal link between reduced CENP-T recruitment and the observed centromere inactivation phenotype. Thus, the Cnp1 N-tail promotes epigenetic stability of centromeres via recruitment of the CENP-T branch of the CCAN. Genome-wide localization of GFP-tagged N-tail Cnp1 variant tailswap versus wt control in cnp1 deletion background
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Project description:We employ the well-studied fission yeast centromere to investigate the function of the CENP-A (Cnp1) N-tail. We show that alteration of the N-tail did not affect Cnp1 loading at centromeres, outer kinetochore formation, or spindle checkpoint signaling, but nevertheless elevated chromosome loss. N-Tail mutants exhibited synthetic lethality with an altered centromeric DNA sequence, with rare survivors harboring chromosomal fusions in which the altered centromere was epigenetically inactivated. Elevated centromere inactivation was also observed for N-tail mutants with unaltered centromeric DNA sequences. N-tail mutants specifically reduced localization of the CCAN proteins Cnp20/CENP-T and Mis6/CENP-I, but not Cnp3/CENP-C. Overexpression of Cnp20/CENP-T suppressed defects in an N-tail mutant, suggesting a causal link between reduced CENP-T recruitment and the observed centromere inactivation phenotype. Thus, the Cnp1 N-tail promotes epigenetic stability of centromeres via recruitment of the CENP-T branch of the CCAN.
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Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.
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Project description:ISWI-family nucleosome remodeling enzymes need the histone H4 N-terminal tail to mobilize nucleosomes. Here we mapped the H4-tail binding pocket of ISWI. Surprisingly the binding site was adjacent to but not overlapping with the docking site of an auto-regulatory motif, AutoN, in the N-terminal region (NTR) of ISWI, indicating that AutoN does not act as a simple pseudosubstrate as suggested previously. Rather, AutoN cooperated with a hitherto uncharacterized motif, termed AcidicN, to confer H4-tail sensitivity and discriminate between DNA and nucleosomes. A third motif in the NTR, ppHSA, was functionally required in vivo and provided structural stability by clamping the NTR to Lobe 2 of the ATPase domain. This configuration is reminiscent of Chd1 even though Chd1 contains an unrelated NTR. Our results shed light on the intricate structural and functional regulation of ISWI by the NTR and uncover surprising parallels with Chd1. Elife. 2017 Jan 21;6. pii: e21477. doi: 10.7554/eLife.21477. [Epub ahead of print]
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Project description:The histone variant H2A.Z is one of the most evolutionally conserved histone variants. In vertebrates, two isoforms, H2A.Z.1 and H2A.Z.2, are identified and are involved in multiple epigenetic regulations. However, the role of H2A.Z in epigenetic regulations largely remains unknown especially in vertebrate. Previously, we derived tetracycline-inducible H2A.Z isofmrs double knockout (DKO) cells by using DT40 cells. With this cell, we showed that H2A.Z DKO leads to defects in mitotic progression and gene expression. To elucidate the function of H2A.Z further, we established genetic complementation system and confirmed that introducing exogenous H2A.Z complemented phenotypes of H2A.Z DKO cells. Given that acetylation of the N-terminal tail of H2A.Z reportedly contributes to significant roles in H2A.Z functions, we introduced two types of H2A.Z mutants, non-acetylable H2A.Z (5KR-H2A.Z) and chimeric H2A.Z in which its N-terminal tail is replaced with that of canonical H2A (H2A-H2A.Z), into H2A.Z DKO cells. These H2A.Z mutants complemented defects in mitotic progression. However, significant transcriptional dysregulation was observed in H2A.Z DKO cells stably expressing 5KR-H2A.Z and H2A-H2A.Z. These results suggest that the core domain and the N-terminal tail of the vertebrate H2A.Z contribute individually to mitotic progression and transcription regulation, respectively.
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