Soluble TL1A is sufficient for activation of death receptor 3

Abstract

Death receptor 3 (DR3) is a typical member of the tumor necrosis factor receptor family, and was initially identified as a T-cell co-stimulatory molecule. However, further studies revealed a more complex and partly dichotomous role for DR3 and its ligand TL1A under (patho)physiological conditions. TL1A and DR3 are not only a driving force in the development of autoimmune and inflammatory diseases, but also play an important role in counteracting these processes through an increase in the number of regulatory T cells. Ligands of the tumor necrosis factor family typically occur in two forms, membrane-bound and soluble, that can differ strikingly with respect to their efficacy in activating their corresponding receptor(s). Ligand-based approaches to activate the TL1A-DR3 pathway therefore require understanding of the molecular prerequisites of TL1A-based DR3 activation. To date, this has not been addressed. Here, we show that recombinant soluble trimeric TL1A is fully sufficient to strongly activate DR3-associated pro- and anti-apoptotic signaling pathways. In contrast to the TRAIL death receptors, which are much better activated by soluble TRAIL upon secondary ligand oligomerization, but similarly to the death receptor tumor necrosis factor receptor 1, DR3 is efficiently activated by soluble TL1A trimers. Additionally, we have measured the affinity of TL1A-DR3 interaction in a cell-based system, and demonstrated TL1A-induced DR3 internalization. Identification of DR3 as a tumor necrosis factor receptor that responds to soluble ligand trimers without further oligomerization provides a basis for therapeutic exploitation of the TL1A-DR3 pathway.

Multifaceted death receptor 3 signaling—promoting survival and triggering death

“…In line with this, subsequent studies demonstrated that cIAP depletion using small molecules mimicking the function of the second mitochondria‐derived activator of caspases (SMAC) disrupted complex I formation and NFκB signaling . Our lab extended these findings and showed that in the absence of cIAPs DR3 stimulation allowed full‐blown apoptosis induction in the leukemia cell lines TF‐1 and Ku812F . Notably, DR3 expression has also been reported in B cells isolated from patients with chronic lymphocytic leukemia .…”

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

“…Fc-FLAG-scTRAIL was generated by in-frame insertion of FLAG-scTRAIL [47] into a pCR3 variant encoding the IgG1 Fc domain and a linker (kind gift from P. Schneider, Department of Biochemistry, University of Lausanne). Recombinant Fc-FLAG-TRAIL was produced in HEK293 cells as previously described for TL1A [48]. …”

Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells

“…As TNFSF15 and IL24 are secreted factors implicated in apoptotic pathways [33, 34], which were upregulated in the paclitaxel-residual cells (Figure 4B, 4J; Figure 5C, 5D), they might sensitize paclitaxel-residual cells to BV6 via an autocrine loop, and thus, could also sensitize naïve or PTX R cells to this inhibitor. To explore this possibility, we incubated naïve and PTX R MDA-MB-231 and SUM159T cells with supernatants of their paclitaxel-residual counterparts and examined their response to BV6.…”