negative regulation of type I interferon-mediated signaling pathway

Definition

Target type: biologicalprocess

Any process that decreases the rate, frequency or extent of a type I interferon-mediated signaling pathway. [GOC:dph]

Negative regulation of type I interferon (IFN)-mediated signaling pathway is a crucial cellular process that dampens the antiviral response triggered by IFN-I. This pathway is initiated upon viral infection, leading to the production of IFN-I cytokines such as IFN-α and IFN-β. These cytokines bind to their cognate receptors on neighboring cells, activating downstream signaling cascades involving JAK-STAT proteins. This ultimately leads to the transcription of interferon-stimulated genes (ISGs), encoding proteins that inhibit viral replication. However, sustained activation of this pathway can be detrimental to the host cell. Therefore, negative regulation is essential to maintain cellular homeostasis and prevent excessive inflammation or immune-mediated damage.

This negative regulation involves various mechanisms, including:

1. **Suppression of IFN-I Production:**
- **Viral evasion strategies:** Some viruses encode proteins that interfere with the production of IFN-I by blocking viral sensing pathways or inhibiting the activation of transcription factors like IRF3 and IRF7.
- **Cellular inhibitors:** Cells express proteins like A20, SOCS1, and USP18, which suppress the activation of signaling pathways involved in IFN-I production.

2. **Inhibition of IFN-I Signaling:**
- **Degradation of signaling proteins:** Ubiquitin ligases like TRIM25 and RNF125 target IFN-I signaling proteins for degradation, reducing their levels.
- **Blockage of JAK-STAT activation:** Proteins like PIAS1 and SHP2 inhibit the phosphorylation and activation of JAK-STAT proteins, preventing downstream signaling.
- **Interference with ISG expression:** Viral proteins or cellular factors can interfere with the transcription or translation of ISGs, reducing the expression of antiviral proteins.

3. **Termination of IFN-I Signaling:**
- **Degradation of IFN-I receptors:** Internalization and degradation of IFN-I receptors limit their availability for ligand binding.
- **Negative feedback loops:** IFN-I itself can induce the expression of negative regulators, creating a feedback loop that limits its own signaling.

In summary, negative regulation of type I interferon-mediated signaling pathway is a complex and tightly regulated process that ensures an appropriate and balanced antiviral response. This involves suppression of IFN-I production, inhibition of IFN-I signaling, and termination of IFN-I signaling. These mechanisms collectively contribute to the fine-tuning of the antiviral response and prevent excessive inflammation or immune-mediated damage to the host.'
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Proteins (3)

Compounds (46)