Target type: biologicalprocess
Any process that stops, prevents, or reduces the frequency, rate, or extent of MyD88-independent toll-like receptor signaling pathway. [GOC:add, PMID:16551253, PMID:17328678]
Negative regulation of MyD88-independent toll-like receptor signaling pathway involves a complex interplay of molecular mechanisms that dampen the activation of this specific immune signaling branch. This pathway, unlike the MyD88-dependent pathway, is primarily activated by TLR3, TLR4, and TLRs 7-9.
Here's a breakdown of the key steps and regulatory elements:
1. **TLR Recognition and Activation:** Upon encountering their respective ligands (e.g., viral dsRNA for TLR3, bacterial LPS for TLR4, or viral ssRNA for TLR7/8/9), these TLRs undergo conformational changes and dimerization.
2. **TRIF-Dependent Signaling:** The activated TLRs recruit the adaptor protein TRIF (TIR domain-containing adapter-inducing interferon-beta), initiating a downstream signaling cascade.
3. **TRAF3 and TBK1 Activation:** TRIF interacts with TRAF3 (TNF receptor-associated factor 3), leading to the activation of TBK1 (TANK-binding kinase 1).
4. **IRF3 Phosphorylation and Nuclear Translocation:** TBK1 phosphorylates the transcription factor IRF3 (interferon regulatory factor 3), promoting its dimerization and translocation to the nucleus.
5. **Type I Interferon Production:** In the nucleus, IRF3 interacts with other transcription factors and induces the transcription of type I interferons (IFN-alpha and IFN-beta).
6. **Negative Regulatory Mechanisms:** A range of mechanisms contribute to the negative regulation of this pathway:
- **Inhibition of TLR Activation:** Certain proteins, like the TLR adaptor protein MAL, can directly inhibit TLR4 activation, dampening the initiation of the signaling cascade.
- **TRAF3 Degradation:** TRAF3 can be targeted for degradation by ubiquitination, effectively reducing its availability for signal transduction.
- **TBK1 Inhibition:** The activity of TBK1 can be negatively regulated by several mechanisms, including phosphorylation by kinases like IKK-epsilon or by interaction with proteins like SARM1.
- **IRF3 Degradation:** Phosphorylated IRF3 can be subject to ubiquitination and proteasomal degradation, limiting its ability to induce interferon production.
- **Negative Feedback Loops:** Type I interferons themselves can induce the expression of negative regulators, such as SOCS1 (suppressor of cytokine signaling 1), which can inhibit downstream signaling components.
- **Crosstalk with Other Pathways:** Signaling pathways mediated by other TLRs (MyD88-dependent) or by other receptors can influence the activity of the MyD88-independent pathway, leading to complex regulatory interactions.
The fine-tuning of MyD88-independent TLR signaling is crucial for maintaining immune homeostasis. Overactivation of this pathway can contribute to excessive inflammation and autoimmune responses, whereas insufficient activation can impair antiviral immunity. Therefore, the intricate network of negative regulatory mechanisms ensures a balanced and controlled response to TLR activation.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| NAD(+) hydrolase SARM1 | An NAD(+) hydrolase SARM1 that is encoded in the genome of human. [PRO:CNA] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| niacinamide | nicotinamide : A pyridinecarboxamide that is pyridine in which the hydrogen at position 3 is replaced by a carboxamide group. | pyridine alkaloid; pyridinecarboxamide; vitamin B3 | anti-inflammatory agent; antioxidant; cofactor; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; EC 3.5.1.98 (histone deacetylase) inhibitor; Escherichia coli metabolite; geroprotector; human urinary metabolite; metabolite; mouse metabolite; neuroprotective agent; Saccharomyces cerevisiae metabolite; Sir2 inhibitor |
| rabeprazole | Rabeprazole: A 4-(3-methoxypropoxy)-3-methylpyridinyl derivative of timoprazole that is used in the therapy of STOMACH ULCERS and ZOLLINGER-ELLISON SYNDROME. The drug inhibits H(+)-K(+)-EXCHANGING ATPASE which is found in GASTRIC PARIETAL CELLS. | benzimidazoles; pyridines; sulfoxide | anti-ulcer drug; EC 3.6.3.10 (H(+)/K(+)-exchanging ATPase) inhibitor |
| phenazopyridine hydrochloride | phenazopyridine hydrochloride : A hydrochloride obtained by combining phenazopyridine with one equivalent of hydrochloric acid. A local anesthetic that has topical analgesic effect on mucosa lining of the urinary tract. Its use is limited by problems with toxicity (primarily blood disorders) and potential carcinogenicity. | hydrochloride | carcinogenic agent; local anaesthetic; non-narcotic analgesic |
| Berberine chloride (TN) | organic molecular entity | ||
| tenatoprazole | Tenatoprazole: structure in first source | imidazopyridine | |
| nitrofurazone | nitrofurazone : A semicarbazone resulting from the formal condensation of semicarbazide with 5-nitrofuraldehyde. A broad spectrum antibacterial drug, although with little activity against Pseudomonas species, it is used as a local application for burns, ulcers, wounds and skin infections. Nitrofurazone: A topical anti-infective agent effective against gram-negative and gram-positive bacteria. It is used for superficial WOUNDS AND INJURIES and skin infections. Nitrofurazone has also been administered orally in the treatment of TRYPANOSOMIASIS. | ||
| dexlansoprazole | Dexlansoprazole: The R-isomer of lansoprazole that is used to treat severe GASTROESOPHAGEAL REFLUX DISEASE. | benzimidazoles; sulfoxide |