negative regulation of necroptotic process

Definition

Target type: biologicalprocess

Any process that decreases the rate, frequency or extent of a necroptotic process, a necrotic cell death process that results from the activation of endogenous cellular processes, such as signaling involving death domain receptors or Toll-like receptors. [GOC:BHF, GOC:dph, GOC:mtg_apoptosis, GOC:tb]

Necroptosis is a programmed form of cell death that is independent of caspases, the main executioners of apoptosis. It is triggered by various stimuli, including TNFα, TLR3/4 agonists, and viral infections. While normally a protective mechanism against pathogens and cellular stress, dysregulation of necroptosis can contribute to various diseases, including neurodegenerative disorders, inflammatory bowel disease, and cancer.

The negative regulation of necroptosis involves multiple mechanisms that act at different levels:

1. **Upstream Inhibition:**
- **Receptor Deactivation:** Receptor interacting protein kinases (RIPKs) are key mediators of necroptosis signaling. Their activation is triggered by the binding of TNFα or other stimuli to the TNFR1 receptor. Negative regulation can occur by inhibiting TNFR1 activation, either through preventing ligand binding or by promoting receptor internalization and degradation.
- **Inhibition of RIPK1 Kinase Activity:** RIPK1 is a central hub in the necroptosis pathway. Its kinase activity is essential for downstream signaling. Negative regulation can occur through various mechanisms, including:
- **Ubiquitination:** Ubiquitination of RIPK1 by cellular ubiquitin ligases, such as cIAP1/2, can prevent its association with RIPK3 and inhibit necroptosis.
- **Phosphorylation:** Specific kinases, such as TAK1, can phosphorylate RIPK1, promoting its association with the NF-κB pathway and inhibiting necroptosis.
- **Degradation:** Proteasomal degradation of RIPK1 can reduce its availability for necroptosis signaling.

2. **Downstream Inhibition:**
- **RIPK3 Inhibition:** RIPK3 is the direct downstream effector of RIPK1 in necroptosis. Inhibition of RIPK3 can be achieved through:
- **Ubiquitination:** Like RIPK1, RIPK3 can be ubiquitinated by cIAP1/2, preventing its interaction with RIPK1 and inhibiting necroptosis.
- **Phosphorylation:** Specific kinases can phosphorylate RIPK3, suppressing its activity and promoting its degradation.
- **MLKL Inhibition:** MLKL is the final executioner protein in the necroptosis pathway. Its oligomerization and translocation to the plasma membrane lead to cell death. Negative regulation of MLKL can occur through:
- **Phosphorylation:** MLKL is phosphorylated by RIPK3, which is necessary for its activation. Specific phosphatases can dephosphorylate MLKL, preventing its activation.
- **Inhibitors:** There are small molecules that can directly inhibit MLKL activity, blocking its interaction with the plasma membrane and preventing cell death.

3. **Cell Survival Mechanisms:**
- **Antioxidant Defense:** Reactive oxygen species (ROS) are important inducers of necroptosis. Increasing antioxidant defenses within the cell can reduce ROS levels and inhibit necroptosis.
- **Autophagy:** Autophagy is a cellular process of self-digestion that can remove damaged organelles and cellular components. This can contribute to negative regulation of necroptosis by clearing potentially damaging molecules.

Overall, the negative regulation of necroptosis is a complex process involving multiple cellular mechanisms that operate at various levels. This intricate regulation ensures that necroptosis is tightly controlled, preventing inappropriate cell death and maintaining cellular homeostasis.
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Proteins (6)

Compounds (107)