Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1175996 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31071500_1.fastq.gz | Fastqsanger.gz | |||
| SRR31071500_2.fastq.gz | Fastqsanger.gz | |||
| SRR31071501_1.fastq.gz | Fastqsanger.gz | |||
| SRR31071501_2.fastq.gz | Fastqsanger.gz | |||
| SRR31071502_1.fastq.gz | Fastqsanger.gz |
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Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in Atg5/7-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
2025-05-07 | PXD057003 | Pride
Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in Atg5/7-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
2025-02-05 | GSE280034 | GEO
Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its evolutionarily conserved domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1-null hematopoietic lineage. The Becn1/STAT3/ISG15 axis remains functional in autophagy-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3/ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
| S-EPMC11785930 | biostudies-literature
Project description:A comprehensive gene expression analysis was performed on a co-culture of breast cancer cells and mesenchymal stromal cells, the latter of which either expressed beclin-1 or was depleted of beclin-1 by siRNA.
2015-02-21 | GSE66154 | GEO
Project description:Chromosomal instability (CIN) is defined by the propensity to acquire structural and/or numerical aberration in the normal cellular karyotype and is often associated with cancer. Autophagy is a catabolic process that leads to the recycling of cellular components that may positively or negatively impact on cancer development and progression, depending on the context. Recent work postulated that the depletion of the pro-autophagic and tumor suppressive protein Beclin 1 triggers CIN by interfering with mitotic chromosome segregation, providing a possible mechanism for how Beclin 1 can act as a tumor suppressor (Fremont et al., PMID: 23478334). Here, we present data supporting the notion that the phenotypes described in Fremont et al., depend on a siRNA off-target effect. The transcriptomic analysis shown here was designed to identify the factor(s) that are responsible for such phenotype. HeLa cells synchronized in mitosis have been transfected in 3 independent experiments with either Beclin 1-ER or Beclin 1-II siRNA. RNA was extracted and subjected to gene expression profiling. Differentially expressed probe sets/genes have been identified between the ER and II siRNA using the moderated t-test from Bioconductor's limma package with the resulting p-values being adjusted for multiple hypothesis testing using the method from Benjamini and Hochberg.
2015-09-02 | E-GEOD-69052 | biostudies-arrayexpress
Project description:We assessed how lack of ISG15 influences the levels of transcripts after IFNa stimulation. Expression data from ISG15 deficient patients (P1, P2, P3) and control (C1, C6, C16) hTert fibroblasts
2014-12-01 | GSE60359 | GEO
Project description:ISG15 counteracts Listeria monocytogenes infection
| PRJEB9655 | ENA
Project description:Immortalized fibroblasts (S1F and R2 cells) were tretaed with or without 300 ng/ml ISG15 for 2 days
2025-10-20 | GSE216151 | GEO
Project description:ISG15 is primarily documented as an interferon-stimulated, ubiquitin-like protein (ubl), which has anti-viral activity. Although ISG15 was the founding member of the ubl protein family, very little is known about its function. We have found that ISG15 expression in non-phagocytic cells is dramatically induced upon Listeria infection and that surprisingly this induction can be Type I Interferon independent. Listeria-mediated ISG15 induction depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection both in vitro and in vivo. We then made use of Stable Isotope Labeling in tissue culture (SILAC) to identify the ISGylated proteins that could be responsible for the ISG15-mediated protective effect. Our SILAC analysis revealed that overexpression of ISG15 leads to a striking ISGylation of integral membrane proteins of the endoplasmic reticulum and Golgi apparatus, which correlates with increased canonical secretion of cytokines. Taken together, our data reveal a previously uncharacterized signaling pathway that restricts Listeria infection and acts via ISGylation, reinforcing the view that ISG15 is a key component of the innate immune arsenal of the mammalian host.
2017-03-29 | MSV000080750 | MassIVE