negative regulation of NF-kappaB transcription factor activity

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of the activity of the transcription factor NF-kappaB. [GOC:dph, GOC:rl, GOC:tb]

NF-κB is a ubiquitous transcription factor that plays a central role in regulating a wide range of cellular processes, including inflammation, immunity, cell proliferation, and apoptosis. NF-κB activation is tightly controlled and its dysregulation can lead to various diseases. Negative regulation of NF-κB activity is crucial for maintaining cellular homeostasis and preventing excessive inflammation. This intricate process involves multiple levels of control, including:

1. **Inhibition of IκB kinase (IKK) complex activation:** IKK is a key enzyme responsible for phosphorylating IκB, leading to its degradation and NF-κB release. Various mechanisms can inhibit IKK activation, including:
- **Inhibitory proteins:** Proteins such as A20, IκBα, and IκBε can directly bind to IKK and suppress its activity.
- **Deubiquitinases (DUBs):** These enzymes remove ubiquitin chains from IKK, preventing its activation.
- **Phosphatases:** Phosphatases can dephosphorylate IKK, inhibiting its kinase activity.
2. **Suppression of NF-κB nuclear translocation:** NF-κB resides in the cytoplasm in an inactive state, bound to IκB. Once IκB is degraded, NF-κB translocates to the nucleus where it binds to DNA and activates gene transcription. Several mechanisms can prevent nuclear translocation, including:
- **Increased IκB expression:** The synthesis of new IκB molecules can sequester NF-κB in the cytoplasm, preventing its nuclear entry.
- **Inhibition of NF-κB nuclear import:** Proteins such as importin-α can block the import of NF-κB into the nucleus.
3. **Negative feedback loops:** NF-κB itself can induce the expression of its own inhibitors, such as A20, which then act to dampen NF-κB activity, creating a negative feedback loop.
4. **Post-translational modifications:** Modifications like acetylation, phosphorylation, and ubiquitination can influence the activity and stability of NF-κB.
5. **MicroRNA-mediated regulation:** MicroRNAs can target and degrade NF-κB mRNA, thereby reducing its expression.

By orchestrating these various regulatory mechanisms, cells can precisely control the duration and intensity of NF-κB signaling. This fine-tuning is critical for maintaining cellular homeostasis and mounting appropriate responses to various stimuli. Disruptions in these negative regulatory pathways can lead to chronic inflammation, autoimmune diseases, and cancer.'
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Proteins (15)

Compounds (575)