Compartmentalization of TNF Receptor 1 Signaling

Abstract

The molecular regulation of the recruitment of initial signaling complexes at the TNF-R1 is poorly defined. We demonstrate here that within minutes internalized TNF-R1 (TNF receptosomes) recruits TRADD, FADD, and caspase-8 to establish the "death-inducing signaling complex" (DISC). In addition, we identified the TNF-R1 internalization domain (TRID) required for receptor endocytosis and provide evidence that TNF-R1 internalization, DISC formation, and apoptosis are inseparable events. Analyzing cell lines expressing an internalization-deficient receptor (TNF-R1 DeltaTRID) revealed that recruitment of RIP-1 and TRAF-2 to TNF-R1 occurred at the level of the plasma membrane. In contrast, aggregation of TRADD, FADD, and caspase-8 to establish the TNF-R1-associated DISC is critically dependent on receptor endocytosis. Furthermore, fusion of TNF receptosomes with trans-Golgi vesicles results in activation of acid sphingomyelinase and cathepsin D. Thus, TNF receptosomes establish the different TNF signaling pathways by compartmentalization of plasma membrane-derived endocytic vesicles harboring the TNF-R1-associated DISC.

Poxvirus Tumor Necrosis Factor Receptor (TNFR)-Like T2 Proteins Contain a Conserved Preligand Assembly Domain That Inhibits Cellular TNFR1-Induced Cell Death

“…TNFR1 transduces a number of other signaling pathways in addition to caspase-mediated apoptotic signaling; TNFR1 can transduce activation of NFB, Jun, and MAP kinase, and TNFR1 induces neutral and acid sphingomyelinase, resulting in the production of ceramide (55). Recent evidence suggests that these pathways appear to be tightly regulated by TNFR internalization (36). Our data indicate that M-T2 prevents TNFR1-induced apoptotic signaling from intracellular locations, and in this regard it will be interesting to determine whether M-T2 affects the recruitment of particular TNFR1-association proteins and hence other TNFR1 signaling pathways.…”

Functional and Physiological Characteristic of RIPK and MLKL in TNF Signaling

“…Stimulation of tumor necrosis factor (TNF)-like cytokines can initiate cellular signaling pathways that control homeostasis and viability in an organism [7,40]. This stimulation is regulated by many protein complexes, including ligand-receptor complex, inhibitor κB kinase (IKK) complex, death-inducing signaling complex, apoptosome, necrosome, transforming growth factor beta-activated kinase-1 (TAK1)/ TAK1-binding protein 2/3, signaling complexes of death domain superfamily and other cytosolic complexes ( Fig.…”

Modulatory role of the anti-apoptotic protein kinase CK2 in the sub-cellular localization of Fas associated death domain protein (FADD)

“…(1)(2)(3)(4)(5) Upon activation of the receptors by their respective ligands, cytoplasmic FADD binds to the intra-cytoplasmic tail of these receptors via its death domain (DD) and transduces the signal to caspase-8 via homotypic binding of their respective death effector domain. As a result, downstream effector caspases are activated and lead to subsequent cell death.…”