negative regulation of canonical NF-kappaB signal transduction

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate or extent of a canonical NF-kappaB signaling cascade. [GOC:jl]

Negative regulation of canonical NF-kappaB signal transduction is a crucial cellular process that dampens the activity of the NF-kappaB signaling pathway, a key mediator of inflammation, immunity, and cell survival. The canonical pathway is triggered by various stimuli, including pro-inflammatory cytokines like TNF-alpha and IL-1, pathogen-associated molecular patterns (PAMPs), and stress signals. Upon activation, the pathway leads to the nuclear translocation of NF-kappaB, a transcription factor complex, which then initiates the transcription of genes involved in inflammatory responses.

Negative regulation of this pathway is essential to prevent excessive inflammation and maintain homeostasis. It involves a complex interplay of various molecular mechanisms that act at different stages of the signaling cascade, ensuring that the NF-kappaB response is tightly controlled and transient.

**1. Receptor-level regulation:**

* **Receptor internalization and degradation:** Stimulated receptors, such as TNF-alpha receptor (TNFR1), can be internalized and degraded via endocytosis. This reduces the availability of receptors for further signaling.

* **Receptor desensitization:** Receptors can become desensitized by phosphorylation, leading to decreased signal transduction efficiency.

**2. Signaling complex assembly and disassembly:**

* **Inhibition of IKK complex activation:** The IKK complex, a key kinase in the NF-kappaB pathway, can be inhibited by various mechanisms. For instance, proteins like A20 and CYLD act as deubiquitinases, removing ubiquitin modifications from proteins involved in IKK activation, thereby suppressing the complex's activity.

* **Suppression of TRAF6 activity:** TRAF6, an E3 ubiquitin ligase, plays a crucial role in IKK activation. Its activity can be suppressed by proteins like A20 and TAX1BP1.

**3. Nuclear translocation of NF-kappaB:**

* **Inhibition of NF-kappaB nuclear translocation:** Proteins like IκBα, the canonical NF-kappaB inhibitor, can bind to and sequester NF-kappaB in the cytoplasm, preventing its nuclear translocation.

* **Active export of NF-kappaB from the nucleus:** Nuclear export signals can be activated, leading to the active transport of NF-kappaB out of the nucleus.

**4. NF-kappaB transcriptional activity:**

* **Direct inhibition of NF-kappaB DNA binding:** Proteins like IκBα can compete with NF-kappaB for DNA binding sites.

* **Recruitment of corepressors:** Corepressors can be recruited to NF-kappaB target genes, preventing the recruitment of transcription coactivators and hindering gene expression.

**5. Induction of anti-inflammatory mediators:**

* **Induction of anti-inflammatory cytokines:** Negative regulation of NF-kappaB can lead to the production of anti-inflammatory cytokines like IL-10, which further suppress inflammation.

* **Upregulation of anti-inflammatory proteins:** Negative regulation of NF-kappaB can upregulate the expression of anti-inflammatory proteins like A20 and CYLD, creating a feedback loop that further dampens the NF-kappaB response.

Overall, negative regulation of canonical NF-kappaB signaling is a multifaceted process that involves a complex interplay of various molecular mechanisms, ensuring the appropriate control of NF-kappaB activity and preventing excessive inflammation.'
"

Proteins (17)

Compounds (427)