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Proteolytic signaling by TNFalpha: caspase activation and IkappaB degradation
1Department of Interdisciplinary Oncology, University of South Florida College of Medicine, H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. hu@moffitt.usf.edu
Abstract:
Following binding its death receptor on the plasma membrane, tumor necrosis factor (TNF) induces the receptor trimerization and recruits a number of death domain-containing molecules to form the receptor complex. The complex promotes activation of downstream caspase cascade and induces degradation of IkappaBalpha. Caspases are activated using mechanisms of oligomeration and 'self-controlled proteolysis'. According to their structures and functions, apoptosis related caspases can be divided into upstream and downstream caspases. In general, upstream caspases cleave and activate downstream caspases by proteolysis of the Asp-X site. Activated caspases then cleaved target substrates. To date, more than 70 proteins have been identified to be substrates of caspases in mammalian cells. Caspases can alter the function of their target proteins by destroying structural components of the cytoskeleton and nuclear scaffold or by removing their regulatory domains. Activation of NF-kappaB is dependent on the degradation of IkappaBalpha. IkappaB kinase (IKK) phosphorylates IkappaBalpha at the residues 32 and 36 followed by polyubiquitination at lysine 21 and 22 and subsequent degradation of the molecules by 26S proteasome. There is extensive crosstalk between the apoptotic and NF-kappaB signaling pathways that emanate from TNF-R1. On the one hand, activation of NF-kappaB can inactivate caspases; on the other hand, activated caspases can inhibit the activation of NF-kappaB. Both processes involve in proteolysis. This crosstalk may be important for maintaining the balance between the two pathways and for determining whether a cell should live or die.
Insights
Tumor necrosis factor (TNF) triggers cell death pathways involving caspases and the NF-kappaB pathway. These signaling cascades exhibit crosstalk, influencing cell survival and apoptosis.
Area of Science:
- Molecular Biology
- Cell Signaling
- Apoptosis
Background:
- Tumor necrosis factor receptor 1 (TNF-R1) activation initiates complex signaling cascades.
- These pathways involve caspase activation, crucial for apoptosis, and NF-kappaB activation, regulating inflammation and survival.
- The interplay between apoptosis and NF-kappaB signaling is critical for cellular fate determination.
Purpose of the Study:
- To elucidate the molecular mechanisms of caspase activation following TNF-R1 engagement.
- To describe the process of IkappaBalpha degradation and subsequent NF-kappaB activation.
- To investigate the crosstalk and reciprocal regulation between apoptotic and NF-kappaB signaling pathways.
Main Methods:
- Analysis of receptor trimerization and recruitment of death domain molecules upon TNF binding.
- Characterization of caspase activation mechanisms, including oligomerization and proteolysis.
- Examination of IkappaBalpha phosphorylation, ubiquitination, and degradation mediated by IKK.
Main Results:
- TNF-R1 activation leads to caspase cascade initiation and IkappaBalpha degradation.
- Caspases, divided into upstream and downstream types, activate via proteolysis and cleave over 70 substrates.
- NF-kappaB activation is dependent on IkappaBalpha degradation, while crosstalk exists where each pathway can inhibit the other.
Conclusions:
- The intricate crosstalk between TNF-R1-mediated apoptotic and NF-kappaB pathways is vital.
- This reciprocal regulation, involving proteolysis, helps maintain cellular homeostasis.
- Understanding this balance is key to determining cell fate, influencing survival versus programmed cell death.