negative regulation of non-canonical NF-kappaB signal transduction

Definition

Target type: biologicalprocess

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

Negative regulation of non-canonical NF-κB signal transduction is a complex biological process that involves the fine-tuning of the NF-κB signaling pathway, specifically targeting the alternative pathway known as the non-canonical NF-κB pathway. This pathway is distinct from the canonical NF-κB pathway and is activated by a different set of stimuli.

The non-canonical NF-κB pathway is primarily triggered by members of the tumor necrosis factor (TNF) superfamily, including lymphotoxin-α (LT-α) and CD40 ligand (CD40L). These ligands bind to their respective receptors, LTβR and CD40, which in turn activate a signaling cascade involving the adaptor protein TRAF3. TRAF3 recruits the kinases NIK (NF-κB-inducing kinase) and IKKα (inhibitor of κB kinase α) to the receptor complex.

NIK activation is crucial for the non-canonical pathway. Once activated, NIK phosphorylates and activates the transcription factor RelB and its partner protein p100. Phosphorylation of p100 promotes its processing by the proteasome into its active form, p52. This processing event is also regulated by the NF-κB inhibitor, IκBα. The p52-RelB dimer then translocates to the nucleus where it binds to specific DNA sequences known as κB sites, regulating the expression of genes involved in various cellular processes, including immune responses, development, and inflammation.

Negative regulation of the non-canonical NF-κB pathway is essential for maintaining cellular homeostasis and preventing excessive inflammation. Several mechanisms contribute to this regulation:

* **Ubiquitination and Degradation of NIK:** NIK is a key regulatory molecule, and its stability is tightly controlled. Upon activation, NIK becomes polyubiquitinated and targeted for degradation by the proteasome. This process is mediated by the E3 ubiquitin ligases TRAF2 and cIAP1, which are recruited to the receptor complex.
* **Inhibition of NIK Activity:** Specific inhibitors of NIK activity, such as the protein A20, can suppress the non-canonical pathway. A20 is a deubiquitinase that removes ubiquitin chains from TRAF3, thereby preventing NIK activation.
* **Regulation of p100 Processing:** The processing of p100 into p52 is also subject to regulation. The deubiquitinase CYLD can inhibit p100 processing by removing ubiquitin chains from NIK. This leads to reduced activation of the non-canonical pathway.
* **Negative Feedback Loops:** The non-canonical pathway itself can induce negative feedback loops. For example, the transcription factors RelB and p52 can activate genes that encode proteins that inhibit NIK activity, thereby dampening the pathway.

In summary, the negative regulation of non-canonical NF-κB signal transduction is a complex and tightly controlled process involving multiple regulatory proteins and mechanisms. This regulation is critical for maintaining cellular homeostasis and preventing uncontrolled inflammation, highlighting the importance of balancing this signaling pathway for proper cellular function.'
"

Proteins (7)

Compounds (371)