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A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes

ABSTRACT: A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes

PROVIDER: PRJNA907842 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22509300.fastq.gz	Fastqsanger.gz
	SRR22509301.fastq.gz	Fastqsanger.gz
	SRR22509302.fastq.gz	Fastqsanger.gz
	SRR22509303.fastq.gz	Fastqsanger.gz
	SRR22509304.fastq.gz	Fastqsanger.gz

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A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes

Project description:Type I interferons (IFN) induce powerful anti-viral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common anti-viral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses, and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.

2022-12-15 | GSE219283 | GEO

A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes.

Project description: Not available

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A stimulus-contingent positive feedback loop enables IFN-β activation of pro-inflammatory genes

Project description: Not available

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Slc44a2 deficiency unveils an IFN-I–dependent feedback control of pDC egress

Project description:Plasmacytoid dendritic cells (pDCs) are a specialized subset of innate immune cells capable of sensing viral nucleic acids and rapidly producing large amounts of type I interferons (IFN-I). However, excessive IFN-I production can cause various immunopathogenic conditions. The capacity for IFN-I production by pDCs is tightly regulated, yet the underlying mechanisms remain incompletely understood. Here, we describe two levels of negative regulatory mechanisms controlling IFN-I production by pDCs. First, we identified SLC44A2 as a negative regulator of IFN-I production. SLC44A2 was highly expressed in resting pDCs but significantly downregulated upon activation. Deficiency of SLC44A2 led to excessive IFN-I production. Mechanistically, SLC44A2 may restrict IFN-I production by exporting threonine, asparagine, and glutamine, amino acids that we found to be essential for IFN-I production in pDCs. Second, we uncovered an IFN-I-dependent negative feedback mechanism controlling pDC egress. Excessive IFN-I restrained pDC migration by downregulating CCR2 and CCR5. This feedback was generally observed during viral infections, autoimmune diseases, and in Slc44a2-deficient mice. Taken together, these two regulatory mechanisms are essential for maintaining pDC homeostasis and preventing systemic overactivation of IFN-I responses.

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Slc44a2 deficiency unveils an IFN-I–dependent feedback control of pDC egress II

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Negative feedback of IFN-I signaling through IFN-competent RIG-I-like receptor-induced HSPA6

Project description:Negative feedback of IFN-I signaling through IFN-competent RIG-I-like receptor-induced HSPA6

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Negative feedback of IFN-I signaling through IFN-competent RIG-I-like receptor-induced HSPA6

Project description:The RIG-I-like receptors (RLRs) form filaments to activate type-I interferon (IFN-I) and NF-KB signaling through their adaptor protein MAVS and downstream cascades. These filaments are recognized and regulated by cell-encoded machinery for correct activation. Here, we identified the stress-sensitive heat shock protein, HSPA6, was induced to express upon RLR-MAVS activation to act as a negative regulator of IFN-I signaling. Interestingly, by using MAVS-KO cells, we showed that HSPA6 was upregulated dependent on the presence of IFN-competent RLRs but not MAVS. Gene knockout (KO) tests indicated that the E3 ligases, stress granules (SGs), and transcription factors IRF1 and AP1 were all shared to induce HSPA6 and the canonical IFNb. Kinetic analysis showed that HSPA6 upregulated slower than IFNb, implicating these two genes competed machinery for transcription activation. Further tests suggested the induced HSPA6 bound to IFN-competent MDA5 to dissolve the filaments and downregulated IFN induction. Thus, our study uncovered a new gene activation mechanism by the IFN-competent RLRs to serve as negative feedback, arguing for a gene regulatory role of functional filaments of innate immunity.

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Project description:Slc44a2 deficiency unveils an IFN-I–dependent feedback control of pDC egress II

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