Table 1.
The major death receptors that induce necroptosis.
| Death ligand | Death receptor | Primary mechanisms for inducing necroptosis | Ref |
|---|---|---|---|
| TNF | TNFR1 | The binding of TNF-α to TNFR1 triggers multiple signaling pathways, including NF-κB, apoptosis, and necroptosis. The core of the necroptosis mechanism is the regulation of the formation of necrosome, a complex consisting of RIPK1, RIPK3, and MLKL | [15, 20] |
| FASL (CD95L) | FAS (CD95) | cIAP deficiency promotes the recruitment of RIPK1 and Fas when caspase-8 is blocked and enhances the formation of the cytosolic ripoptosome complex, which induces necroptosis | [16] |
| TRAIL | TRAIL1/2 (DR4/5) | The combination of TRAIL to DR4/5 subsequently binds to FADD through the intercellular DD domain, leading to the formation of DISC directly. Then induce necroptosis via non-canonical recruitment of RIPK1. | [147] |
| dsRNA (polyI:C) | TLR3 | TLR3 and TLR4 activate RIPK3 and participate in ensuing necroptosis via TRIF or Myd88. The c-terminal RHIM motif is required for RIPK3 to interact with TRIF or Myd88. The RIPK3/TRIF signaling complex recruits and phosphorylates MLKL, inducing ROS accumulation and mediating TLR3- and TLR4-induced necroptosis | [63] |
| LPS | TLR4 | ||
| IFNα/β/γ | IFNAR1 | In bone-marrow-derived macrophages type, I IFNα and IFNβ bind to their cognate receptor IFNα/β receptor subunit 1 (IFNAR1) to activate Janus kinase 1 and form the IFN-stimulated gene factor 3 (ISGF3) complex. The ISGF3 complex promotes the induction and activation of necrosomes and triggers necroptosis in a transcription-dependent pathway. | [17, 65] |
| Virus (viral dsDNA) | ZBP1 (DAI) | Cytoplastic nucleic acid sensor Z-DNA binding protein 1(ZBP1; also known as DAI) can identify viral dsDNA, promote the recruitment of RIPK3 to form necrosomes without RIPK1, and induce RIPK3-dependent necroptosis | [18, 66, 67] |
| TWEAK | Fn14 | TWEAK-induced apoptosis through the activation of the Fn14 receptor, Caspase inhibitors prevent TWEAK-induced apoptosis but sensitize to necroptosis via the generation of reactive oxygen species. | [5] |
TNF tumor necrosis factor, TNFR1 tumor necrosis factor receptor 1, FASL CD95L, FAS CD95, TRAIL tumor necrosis factor-related apoptosis-inducing ligand, TLR3 Toll-like receptor 3, ZBP1 Z-DNA binding protein 1, TWEAK TNF-like weak inducer of apoptosis, Fn14 fibroblast growth factor-inducible 14