Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL*

By William J. Kaiser, Haripriya Sridharan, Chunzi Huang, P. Mandal, J. Upton, P. Gough, C. Sehon, R. Marquis, J. Bertin, E. Mocarski. Journal of Biological Chemistry, 2013

881 citations recorded by the source corpus.

Background: RIP3-dependent programmed necrosis is an alternative to apoptosis. Results: When caspase-8 is compromised, TRIF-dependent TLRs directly activate RIP3 kinase through RHIM-dependent interactions. Conclusion: TRIF mediates direct RHIM-dependent signaling, triggering necrosis via RIP3 and MLKL. Significance: Programmed necrosis eliminates cells following stimulation of either MyD88 or TRIF signaling pathways that converge on RIP3. Toll-like receptor (TLR) signaling is triggered by pathogen-associated molecular patterns that mediate well established cytokine-driven pathways, activating NF-κB together with IRF3/IRF7. In addition, TLR3 drives caspase 8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling. We find that inhibition or elimination of caspase 8 during stimulation of TLR2, TLR3, TLR4, TLR5, or TLR9 results in receptor interacting protein (RIP) 3 kinase-dependent programmed necrosis that occurs through either TIR domain-containing adapter-inducing interferon-β (TRIF) or MyD88 signal transduction. TLR3 or TLR4 directly activates programmed necrosis through a RIP homotypic interaction motif-dependent association of TRIF with RIP3 kinase (also called RIPK3). In fibroblasts, this pathway proceeds independent of RIP1 or its kinase activity, but it remains dependent on mixed lineage kinase domain-like protein (MLKL) downstream of RIP3 kinase. Here, we describe two small molecule RIP3 kinase inhibitors and employ them to demonstrate the common requirement for RIP3 kinase in programmed necrosis induced by RIP1-RIP3, DAI-RIP3, and TRIF-RIP3 complexes. Cell fate decisions following TLR signaling parallel death receptor signaling and rely on caspase 8 to suppress RIP3-dependent programmed necrosis whether initiated directly by a TRIF-RIP3-MLKL pathway or indirectly via TNF activation and the RIP1-RIP3-MLKL necroptosis pathway.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4202dce806780e34a0daa77d749452d1bdf33248

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Citations in the corpus

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “In addition, Toll-like receptors (TLRs) can also initiate necroptosis via RIPK3 and MLKL phosphorylation independent of RIPK1 kinase activity [75,76].”
Necroptosis: a regulated inflammatory mode of cell death (2018, background): “TLR3 and TLR4 also initiate the necroptosis mediated by TRIF and RIPK3 [40, 41].”
Necroptosis: Mechanisms and Relevance to Disease (2016, neutral): “The coadministration of polyI:C and Z-VAD-fmk may also trigger a necroptotic response mediated by the TLR3 → TRIF → RIPK3 signaling axis in cultured CT26 mouse colorectal carcinoma cells (191).”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Granzyme B (GZMB) acts at the same site to cleave GSDME, activating caspaseindependent pyroptosis in target cells.31,112 Similarly, GSDMB is cleaved by CASP1113 or granzyme A (GZMA).114 Here is not detailed explanation of GSDMA/C-mediated pyroptosis.115 In the typical inflammasome activation pathway”
The role of necroptosis in cancer biology and therapy (2019, background): “[62] demonstrated that Toll like receptor 3/4 (TLR-3/4) induced necroptosis in certain cells is independent of RIPK1 but still depends on both RIPK3 and MLKL.”
Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection (2018, background): “In recent years necroptosis has similarly been shown to occur downstream of TLR signaling (8).”
Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “The data from Wang et al. have revealed that the epigenetic repression of RIPK3 allows NSCLC cell lines to escape from necroptosis, which subsequently increases resistance to chemotherapy [331].”