Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8

Abstract

We have recently shown that stimulation of TNF-R2 selectively enhances apoptosis induction by the death receptor TNF-R1. Here, we demonstrate that stimulation of CD30 or CD40 also leads to selective enhancement of TNF-R1-induced cell death. Enhancement of apoptosis was correlated with the depletion of endogenous TRAF2 within 1 to 6 hours. Selective prestimulation of TNF-R2 for several hours inhibited TNF-R2-induced activation of the anti-apoptotic NF-κB pathway up to 90% and dramatically enhanced apoptosis induction by this receptor. When both TNF-receptors were stimulated simultaneously, TNF-R1-induced NF-κB activation remained unaffected but TNF-R1-induced apoptosis was still significantly enhanced. Compared with FasL-induced cell death TNF-R1-induced activation of caspase-8 was significantly weaker and delayed. Costimulation or prestimulation of TNF-R2 enhanced caspase-8 processing. Life cell imaging and confocal microscopy revealed that both TNF-R1 and TNF-R2 recruited the anti-apoptotic factor cIAP1 in a TRAF2-dependent manner. Thus, TNF-R2 may compete with TNF-R1 for the recruitment of newly synthesized TRAF2-bound anti-apoptotic factors, thereby promoting the formation of a caspase-8-activating TNF-R1 complex. Hence,TNF-R2 triggering can interfere with TNF-R1-induced apoptosis by inhibition of NF-κB-dependent production of anti-apoptotic factors and by blocking the action of anti-apoptotic factors at the post-transcriptional level.

The host inflammatory response contributes to disease severity in Crimean-Congo hemorrhagic fever virus infected mice

“…The default signaling pathway of TNFA-Rs is cell survival in a process regulated by TNF Receptor Associated Factor 2 (TRAF2) [ 42 ]. Continuous activation of either of the two TNFA-Rs, such as during aberrant inflammation, can incur a TRAF2 deficiency that disrupts negative regulation of the death domains associated with TNFA-R1, thereby leading to death pathway signaling [ 43 ]. We predict that CCHFV replication and extensive TNFA-R activation consumes TRAF2 in both hepatocytes and Kupffer cells, subsequently driving signaling pathways towards cell death.…”

Understanding the functional role of membrane confinements in TNF-mediated signaling by multiscale simulations

“…Interestingly, it has been found that the signaling outcome of different TNFR1-mediated pathways can be modulated by TNFR2. For instance, activation of TNFR2 can lead to a significant depletion of cytosolic TRAF2-cIAP1/2 complexes, thus switching the TNFR1-mediated signaling to cell death 72 . We speculate that the differences in TNFR1 and TNFR2’s responds to membrane-bound and soluble ligands are resulted from the conformational dynamics of the two receptors, which further affects the kinetics of their ligand binding and clustering.…”

Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA)

“…A possible reason for cIAP1/TRAF2-depletion in macrophages could be signaling through TNFR2 [ 39 ]. Oligomerized TNFR2 recruits TRAF2 along with TRAF1 and cIAP1/2, leading to NF-κB activation, but also depletes TRAF2-cIAP1/2 complexes in the cytoplasm [ 40 , 41 ]. The largely TNF-independent cIAP1/TRAF2-depletion in our system however pointed to a TNFR2-independent mechanism.…”