Table 1 The major death receptors that induce necroptosis.

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]