regulation of necroptotic process

Definition

Target type: biologicalprocess

Any process that modulates 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 caspase activation and characterized by distinct morphological and biochemical features. It plays a crucial role in various physiological and pathological processes, including development, inflammation, and tissue homeostasis. The regulation of necroptosis is a complex process involving multiple signaling pathways, key proteins, and regulatory mechanisms.

Here's a detailed breakdown of the biological process of necroptosis regulation:

**1. Initiation and Activation:**

* **Receptor Activation:** Necroptosis is often triggered by the activation of death receptors, such as TNF receptor 1 (TNFR1), Fas, and TRAIL receptor, in response to various stimuli, including TNFα, Fas ligand, and TRAIL.
* **RIP Kinase Complex Formation:** Upon receptor activation, a complex of proteins known as the RIP1/RIP3 necrosome forms. This complex comprises receptor-interacting protein kinase 1 (RIP1), receptor-interacting protein kinase 3 (RIP3), and other adaptor proteins.
* **RIP1 Kinase Activity:** RIP1 is a critical component of the necrosome and possesses both kinase and ubiquitin ligase activity. Its kinase activity is crucial for initiating the necroptotic signaling cascade.

**2. Necrosome Assembly and Amplification:**

* **RIP3 Recruitment:** RIP3 is recruited to the necrosome through its interaction with RIP1. This interaction is facilitated by RIP1 kinase activity.
* **RIP3 Activation:** Once recruited to the necrosome, RIP3 undergoes autophosphorylation and activation. RIP3 kinase activity is essential for downstream necroptotic signaling.
* **Necrosome Amplification:** The activated RIP3 kinase phosphorylates other RIP3 molecules within the necrosome, leading to its amplification and the formation of a larger, highly active signaling complex.

**3. Downstream Signaling and Execution:**

* **MLKL Activation:** The RIP3 kinase in the necrosome phosphorylates mixed lineage kinase domain-like protein (MLKL), a crucial effector of necroptosis.
* **MLKL Oligomerization and Translocation:** Upon phosphorylation by RIP3, MLKL undergoes oligomerization and translocates to the plasma membrane.
* **Plasma Membrane Permeabilization:** The oligomerized MLKL at the plasma membrane disrupts its integrity, leading to membrane permeabilization and the release of cellular contents.

**4. Regulation and Inhibition:**

* **Caspase-8 Inhibition:** Necroptosis is regulated by the activity of caspase-8. When caspase-8 is active, it can cleave RIP1 and prevent the formation of the RIP1/RIP3 necrosome, thus inhibiting necroptosis.
* **Cellular Stress and Necroptosis Induction:** Under conditions of cellular stress, such as hypoxia, oxidative stress, and nutrient deprivation, caspase-8 activity may be inhibited, leading to the activation of necroptosis.
* **Necroptosis Inhibitors:** Various pharmacological inhibitors, such as necrostatin-1 (Nec-1) and GSK'873, target RIP1 and RIP3 kinase activity, respectively, inhibiting the formation of the necrosome and blocking necroptosis.

**5. Biological Significance:**

* **Development:** Necroptosis plays a role in the development of various tissues, including the nervous system and the immune system.
* **Inflammation:** Necroptosis contributes to the inflammatory response by releasing damage-associated molecular patterns (DAMPs) that activate the immune system.
* **Tissue Homeostasis:** Necroptosis is essential for maintaining tissue homeostasis by eliminating damaged or infected cells.
* **Disease Pathogenesis:** Necroptosis is involved in the pathogenesis of various diseases, including neurodegenerative diseases, inflammatory bowel disease, and cancer.

The regulation of necroptosis is a complex and finely tuned process that involves multiple signaling pathways, regulatory proteins, and cellular stress responses. Understanding the intricacies of this process is crucial for developing novel therapeutic strategies for diseases associated with aberrant necroptosis.'
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Proteins (6)

Compounds (14)