Interplay between TNF/TNFR1 complex I and complex II signalling pathways

TNF stimulation activates a series of complex signalling cascades that drive cell-fate decisions. The intricate interplay between these signalling pathways plays a pivotal role in determining a cell’s response to TNF. There are several checkpoints throughout TNF/TNFR1 signalling where crosstalk can occur. 1 One of the primary components believed to govern the interplay between TNF/TNFR1 complex I- and complex II-mediated signalling occurs during the early stages of complex formation. The post-translational modification (PTM) profile of RIPK1 determines whether signalling will predominantly propagate from complex I or complex II [97]. Under specific conditions, RIPK1 can experience significant PTM alterations, causing it to dissociate from TNF/TNFR1 complex I and instead form complex IIa. 2 The PTM profile of RIPK1 is thought to be regulated by the antagonistic interactions of A20 and CYLD. A20 binds to M1-linked chains on RIPK1 and protects them from degradation by CYLD, thus stabilising complex I. If CYLD successfully removes M1-linked ubiquitin, RIPK1 is more likely to dissociate from complex I and form complex IIa. 3 TNF/TNFR1 complex I-driven activation of NF-κB leads to increased expression of pro-survival genes, such as cIAP1/2 and c-FLIP. c-FLIP directly inhibits activation of pro-caspase 8, thus reducing signalling downstream of complex IIa. A20 is also under NF-κB transcriptional control, adding another layer of complexity to TNF/TNFR1 signalling crosstalk

Publication

Cellular heterogeneity in TNF/TNFR1 signalling: live cell imaging of cell fate decisions in single cells (2024) Marcus K. Preedy, et al. Cell Death Dis. 2024 Mar;15(3). Figure: F3. Homo sapiens

Disease mentions