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Crosstalk between NF-kappaB-activating and apoptosis-inducing proteins of the TNF-receptor complex
1Unit for Molecular Signal Transduction in Inflammation, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, K. L. Ledeganckstraat 35, Ghent, B-9000, Belgium.
Abstract:
The cytokine tumor necrosis factor (TNF) elicits a wide range of biological responses, including inflammation, cell proliferation, differentiation, and apoptosis. Although the molecular mechanisms of TNF signaling have been largely elucidated, the principle that regulates the balance of life and death is still unknown. This review will focus on the crosstalk that exists between proteins of the TNF receptor (TNF-R) signalosome, and which are involved in the initiation of nuclear factor kappa B (NF-kappaB) activation or apoptosis. At least four different mechanisms of regulation can be distinguished: (i) NF-kappaB-mediated induction of proteins of the TNF-R complex; (ii) NF-kappaB-independent protection against apoptosis by the TNF-R-associating factor 2 (TRAF2)-mediated recruitment of antiapoptotic proteins; (iii) dual activation of apoptosis and NF-kappaB by a single molecule; and (iv) amplification of the death signal by proteolytic inactivation of signaling proteins that are involved in NF-kappaB activation or cell survival.
Insights
Tumor necrosis factor (TNF) signaling balances cell life and death through complex protein interactions within the TNF receptor (TNF-R) signalosome. This review details four key regulatory mechanisms governing these opposing cellular fates.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Tumor necrosis factor (TNF) is a key cytokine regulating critical cellular processes like inflammation, proliferation, differentiation, and apoptosis.
- While TNF signaling pathways are well-studied, the precise mechanisms controlling the balance between cell survival and death remain incompletely understood.
Purpose of the Study:
- To review the intricate crosstalk between proteins in the TNF receptor (TNF-R) signalosome.
- To elucidate regulatory principles governing the initiation of nuclear factor kappa B (NF-kappaB) activation and apoptosis.
- To highlight the molecular basis for the balance between cell survival and programmed cell death.
Main Methods:
- Literature review focusing on protein-protein interactions within the TNF-R signalosome.
- Analysis of signaling pathways involved in NF-kappaB activation and apoptosis.
- Identification and categorization of regulatory mechanisms governing TNF-induced cellular fate.
Main Results:
- Four distinct regulatory mechanisms governing TNF-R signalosome function were identified.
- These include NF-kappaB-mediated induction of TNF-R complex proteins.
- NF-kappaB-independent anti-apoptotic signaling via TRAF2, dual apoptosis/NF-kappaB activation by single molecules, and signal amplification through proteolytic inactivation were also detailed.
Conclusions:
- The balance of cell life and death in TNF signaling is regulated by complex crosstalk within the TNF-R signalosome.
- Understanding these intricate molecular interactions is crucial for deciphering cellular fate decisions.
- This review provides a framework for comprehending the multifaceted regulation of TNF-induced apoptosis and NF-kappaB activation.