I have some questions about TNFalpha that I am a little confused on. When you have TNFalpha binding on the cell…how does the cell decide which route to take. By route…I mean either inflammation or apoptosis. I have been reading in the literature about this…and what I have found is that once TNFalplha binds to its cognate receptor…it can recruit different adaptor proteins such as FADD, TRADD, etc. I know that FADD has a DED domain which can interact with the DED domain in procaspase 8 to activate it thus initiating apoptosis to happen.
On the other hand, I have found that if the right adaptor proteins are recruiting you can also activate NFkappaB which can then translocate into the nucleus and transcribe anti-apoptotic factors such as Bcl-2, c-FLIP, etc.
This is a Complex Signaling Pathway and highly regulated too.
When TNFα binds to TNFR1 (a trimeric receptor), it induces receptor trimerization and initiates a signaling cascade by recruiting various adaptor proteins to its intracellular death domain (DD). This forms the TNFR1 signaling complex, also known as Complex I leading to Pro-survival/Inflammatory Signaling.
If Complex I signaling is disrupted or if deubiquitination of RIPK1 occurs (e.g., by the action of deubiquitinating enzymes like CYLD or A20), the complex transitions to Complex II, which can lead to apoptosis.
However, These pathways are not strictly binary; there is significant crosstalk between survival and death signals. The decision often depends on:
Strength and Duration of TNFα Signal: A transient signal might favor survival, while a prolonged signal could tip the balance towards apoptosis.
Cell Type: Different cells have varying thresholds and regulatory mechanisms for these pathways.
Other Signaling Molecules: Concurrent signals (e.g., from other cytokines or growth factors) can modulate the TNFα-induced response.