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Regulated commitment of TNF receptor signaling: a molecular switch for death or activation
1Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA.
Abstract:
Tumor necrosis factor receptor (TNFR) superfamily members can induce a context-dependent apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. We show that in T cells, TNFR2 (TNFRSF1B) signaling is dramatically affected by the intracellular mediator RIP, a protein Ser/Thr kinase required for NF-kappaB activation by TNFR1 (TNFRSF1A). In the presence of RIP, TNFR2 triggers cell death, whereas in the absence of RIP, TNFR2 activates NF-kappaB. RIP is induced during IL2-driven T cell proliferation, and its inhibition reduces susceptibility to TNF-dependent apoptosis. Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 and TNFR2 as apoptotic mediators.
Insights
Tumor necrosis factor receptor superfamily member 2 (TNFR2) signaling in T cells can trigger cell death or NF-kappaB activation. The intracellular mediator RIP dictates this outcome, influencing T cell apoptosis susceptibility.
Area of Science:
- Immunology
- Cell Biology
- Molecular Signaling
Background:
- Tumor necrosis factor receptor (TNFR) superfamily members mediate diverse cellular responses, including apoptosis and activation.
- The precise mechanisms governing the selection between these opposing signaling pathways remain incompletely understood.
- TNFR superfamily members, TNFR1 (TNFRSF1A) and TNFR2 (TNFRSF1B), play critical roles in immune cell function.
Purpose of the Study:
- To elucidate the intracellular mechanisms that determine context-dependent signaling outcomes of TNFR2.
- To investigate the role of the intracellular mediator RIP in TNFR2-mediated apoptosis and NF-kappaB activation in T cells.
Main Methods:
- Investigated TNFR2 signaling in T cells using molecular biology techniques.
- Analyzed the role of the protein Ser/Thr kinase RIP in modulating TNFR2 downstream signaling.
- Assessed the impact of RIP induction during IL2-driven T cell proliferation on apoptosis susceptibility.
Main Results:
- TNFR2 signaling outcome is significantly influenced by the intracellular mediator RIP.
- In the presence of RIP, TNFR2 signaling leads to T cell death.
- In the absence of RIP, TNFR2 signaling activates NF-kappaB in T cells.
- RIP expression is induced during IL2-driven T cell proliferation, and its inhibition decreases susceptibility to TNF-dependent apoptosis.
Conclusions:
- Intracellular constraints, specifically the presence or absence of RIP, shape the signaling outputs of TNFR2.
- These findings help reconcile conflicting observations regarding the roles of TNFR1 and TNFR2 as mediators of apoptosis.
- The study highlights the critical role of RIP in determining T cell fate in response to TNFR2 stimulation.