ripoptosome assembly

Definition

Target type: biologicalprocess

The aggregation, arrangement and bonding together of a set of components to form a ripoptosome, a protein complex whose formation can induce an extrinsic apoptotic signaling pathway or a necroptotic signaling pathway. The composition of this protein complex may depend on several factors including nature of the signal, cell type and more. [GOC:mtg_apoptosis, PMID:22274400]

Ripoptosome assembly is a complex process that involves the formation of a signaling platform at the plasma membrane, leading to caspase-8 activation and subsequent apoptosis. This process is triggered by various stimuli, including TNF-α, TRAIL, and Fas ligand. Here's a detailed description:

1. **Ligand Binding and Receptor Trimerization:** The process begins with the binding of death ligands (TNF-α, TRAIL, Fas ligand) to their respective death receptors (TNFR1, TRAIL-R1/R2, Fas). This binding event induces receptor trimerization, bringing together three receptor molecules to form a signaling complex.

2. **Recruitment of Adaptor Proteins:** The trimerized death receptors recruit adaptor proteins like TRADD (TNF Receptor Associated Death Domain) and FADD (Fas-Associated Death Domain). These adaptor proteins contain death domains (DDs) that allow them to interact with the death receptors and with each other.

3. **Formation of the DISC (Death-Inducing Signaling Complex):** The assembly of the death receptor, adaptor proteins, and procaspase-8 forms the DISC. This complex acts as a platform for the activation of caspase-8.

4. **Caspase-8 Activation:** Procaspase-8 molecules within the DISC are brought into close proximity, allowing them to auto-activate through proteolytic cleavage. Active caspase-8 is crucial for the initiation of the apoptotic cascade.

5. **RIP1 Kinase Activity and RIP1-RIP3 Interaction:** In addition to caspase-8 activation, the DISC also recruits RIP1 (Receptor Interacting Protein 1). RIP1 can be phosphorylated, leading to its activation. Activated RIP1 can interact with RIP3 (Receptor Interacting Protein 3) to form the necrosome.

6. **Necrosome Formation and Cell Death:** The necrosome complex is formed by RIP1, RIP3, and MLKL (Mixed Lineage Kinase Like). MLKL undergoes phosphorylation by RIP3, becoming activated and leading to membrane permeabilization and cell death through a process known as necroptosis.

7. **RIP1-mediated Inhibition of RIP3:** In certain contexts, RIP1 can also inhibit the formation of the necrosome by preventing the RIP1-RIP3 interaction. This can occur through the phosphorylation of RIP1 by the kinase TAK1 (TGF-β-activated kinase 1).

8. **Regulation of Ripoptosome Assembly:** The assembly of the ripoptosome is tightly regulated by various factors, including cellular stress, cytokine signaling, and post-translational modifications of its components.

9. **Crosstalk with other Signaling Pathways:** Ripoptosome assembly can interact with other cellular signaling pathways, including the NF-κB pathway and the MAPK pathway.

10. **Consequences of Ripoptosome Assembly:** The outcome of ripoptosome assembly can vary depending on the cellular context and the specific stimuli involved. It can lead to caspase-8 activation and apoptosis, the formation of the necrosome and necroptosis, or the activation of pro-inflammatory signaling pathways.'
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Proteins (1)

Compounds (82)