negative regulation of type II interferon-mediated signaling pathway

Definition

Target type: biologicalprocess

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

Negative regulation of type II interferon (IFN-γ)-mediated signaling pathway involves a complex interplay of molecular mechanisms that dampen the downstream effects of IFN-γ, ensuring a tightly controlled and balanced immune response. This process is crucial to prevent excessive inflammation and tissue damage while maintaining immune surveillance.

Here's a detailed description of key steps:

1. **IFN-γ Receptor Binding:** The process begins with IFN-γ binding to its receptor, IFNGR, a heterodimer composed of IFNGR1 and IFNGR2 subunits. This binding triggers receptor dimerization and activation of the associated Janus kinase (JAK) family members, JAK1 and JAK2.

2. **JAK Kinase Activation and Phosphorylation:** Activated JAKs phosphorylate each other, as well as the cytoplasmic tails of the IFNGR subunits. These phosphorylation events create docking sites for the signal transducer and activator of transcription (STAT) proteins, STAT1 and STAT2.

3. **STAT1 and STAT2 Dimerization and Nuclear Translocation:** STAT1 and STAT2 are recruited to the phosphorylated receptor tails, where they are themselves phosphorylated by the activated JAKs. Phosphorylated STAT1 and STAT2 dimerize and translocate from the cytoplasm to the nucleus.

4. **Transcriptional Activation and Gene Expression:** In the nucleus, the STAT1/STAT2 dimer interacts with interferon regulatory factor 9 (IRF9), forming the IFN-stimulated gene factor 3 (ISGF3) complex. ISGF3 binds to IFN-stimulated response elements (ISREs) within the promoters of target genes, initiating their transcription and expression.

5. **Negative Regulation: Suppression of IFN-γ Receptor Signaling:** Negative regulation occurs at multiple points along this signaling pathway, ensuring proper control of IFN-γ-mediated responses:

* **SOCS Family Proteins:** Suppressor of cytokine signaling (SOCS) proteins, particularly SOCS1 and SOCS3, are induced by IFN-γ signaling. They bind to and inhibit the JAKs, preventing further phosphorylation of the receptor and STAT proteins.
* **SHP-1 and SHP-2:** These protein tyrosine phosphatases dephosphorylate the JAKs and the receptor, further dampening the signaling cascade.
* **CIS:** Cytokine-inducible SH2-containing protein (CIS) is another negative regulator that binds to and inhibits JAK1.
* **Ubiquitination and Proteasomal Degradation:** Components of the IFN-γ signaling pathway, including the receptor and STAT proteins, can be targeted for ubiquitination and subsequent degradation by the proteasome, leading to a decrease in signaling strength.
* **Feedback Inhibition:** Some target genes induced by IFN-γ signaling encode negative regulators, creating a feedback loop that limits the duration and amplitude of the signaling response.

6. **Consequences of Negative Regulation:** Proper regulation of IFN-γ signaling is crucial for maintaining immune homeostasis. Excessive IFN-γ signaling can lead to:

* **Autoimmunity:** Uncontrolled IFN-γ production can contribute to the development of autoimmune diseases by promoting inflammation and tissue damage.
* **Chronic Inflammation:** Persistent IFN-γ signaling can contribute to chronic inflammatory conditions.
* **Tissue Damage:** Excessive IFN-γ activity can induce apoptosis and tissue damage.

In summary, negative regulation of IFN-γ signaling is a complex process involving multiple molecular mechanisms that ensure a balanced and controlled immune response. These mechanisms are essential for preventing excessive inflammation, tissue damage, and the development of autoimmune diseases while maintaining the ability to effectively combat pathogens.'"

Proteins (6)

Compounds (187)