regulation of non-canonical NF-kappaB signal transduction

Definition

Target type: biologicalprocess

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

The regulation of non-canonical NF-κB signaling is a complex process involving multiple steps and key players. It is distinct from the canonical pathway and primarily relies on the activation of NF-κB2 (p100) and its processing into the active NF-κB2 (p52) subunit.

Here's a detailed breakdown:

1. **Stimulus Recognition:** This pathway is triggered by a variety of stimuli, including:
* **Lymphotoxin-α (LTα):** This cytokine binds to its receptor, LTβR, on cells like lymphocytes and stromal cells.
* **CD40 Ligand (CD40L):** A protein expressed on activated T cells that binds to CD40 on antigen-presenting cells (APCs).
* **B cell activating factor (BAFF):** A cytokine involved in B cell survival and maturation.
* **Other Signals:** Some bacterial and viral signals can also activate this pathway.

2. **Upstream Signaling Cascade:** Upon stimulus binding, a signaling cascade is initiated:
* **Receptor Complex Formation:** LTβR, CD40, or BAFF receptor complex with TRAF2 and TRAF3 adaptor proteins.
* **IKKα Kinase Activation:** TRAF2/3 recruit and activate the IKKα kinase.
* **NF-κB2 (p100) Phosphorylation:** IKKα directly phosphorylates NF-κB2 (p100) at multiple sites.

3. **p100 Processing:** Phosphorylated NF-κB2 (p100) undergoes ubiquitination and is transported to the proteasome for processing.
* **Ubiquitination:** TRAF2/3 recruit the E3 ubiquitin ligase complex, comprising cIAPs (cellular inhibitor of apoptosis proteins) and the E2 ligase Ubc5, to ubiquitinate p100. This ubiquitination is necessary for proteasome targeting.
* **Proteasomal Degradation:** The ubiquitinated p100 is degraded by the proteasome, resulting in the removal of its C-terminal domain, which contains a repressive domain.

4. **p52 Generation and Nuclear Translocation:** The degradation of p100 generates p52, the active form of NF-κB2.
* **RelB Heterodimerization:** p52 forms a heterodimer with the RelB subunit of the NF-κB family.
* **Nuclear Translocation:** The p52/RelB heterodimer translocates to the nucleus, where it acts as a transcription factor.

5. **Transcriptional Regulation:** The p52/RelB complex binds to specific DNA sequences called κB sites in the promoter regions of target genes. It then activates the transcription of these genes, influencing cellular processes like:
* **Lymphocyte development and differentiation:** Regulating the production and survival of specific immune cells.
* **Secondary lymphoid organ formation:** Controlling the development of lymph nodes and Peyer's patches.
* **Immune response regulation:** Modulating immune responses against pathogens and inflammation.
* **Cell survival and apoptosis:** Influencing the programmed cell death pathways.

6. **Negative Regulation:** The non-canonical pathway also involves mechanisms for negative regulation:
* **Degradation of TRAF2/3:** TRAF2/3 can be degraded by the proteasome, limiting the duration of the signal.
* **Inhibition of IKKα:** A protein called IKKα-N, which lacks the kinase domain, can inhibit IKKα activity.
* **Negative feedback loops:** Some of the genes activated by p52/RelB encode proteins that inhibit the pathway, preventing its overactivation.

In summary, the non-canonical NF-κB pathway is a crucial regulatory process that involves a complex interplay of proteins, kinases, and ubiquitin ligases. It controls a diverse set of cellular functions, especially in the context of immune responses and development.'
"

Proteins (5)

Compounds (25)