PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway activation.

Necroptosis is a recently identified programmed cell death, which is initiated by receptor-interacting serine/threonine-protein kinase 1 (RIP1), RIP3 and mixed-lineage kinase domain-like protein (MLKL). It has been reported that necroptosis induced by tumor necrosis factor (TNF) was inhibited by the inhibitor of phosphatidylinositol-3-kinase (PI3K) and its substrate protein AKT, indicating that PI3K-AKT signaling pathway was involved in mediating TNF-induced necroptosis, whereas it is unclear how PI3K initiates necroptosis. In this study, we found that TNF-induced necroptosis was inhibited by chemical inhibition or genetic deletion of PI3K.

TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor.

As a programmed necrotic cell death, necroptosis has the intrinsic initiators, including receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and mixed-lineage kinase domain-like protein (MLKL), which combine to form necroptotic signaling pathway and mediate necroptosis induced by various necroptotic stimuli, such as tumor necrosis factor (TNF). Although chemical inhibition of RIPK1 blocks TNF-induced necroptosis, genetic elimination of RIPK1 does not suppress but facilitate necroptosis triggered by TNF. Moreover, RIPK3 has been reported to mediate the RIPK1-independent necroptosis, but the involved mechanism is unclear.

TRADD mediates the tumor necrosis factor-induced apoptosis of L929 cells in the absence of RIP3.

Receptor-interacting protein kinase 3 (RIP3) is a critical initiator in mediating necroptosis induced by tumor necrosis factor alpha (TNFα) in L929 cells, so knockdown of RIP3 inhibits TNFα-induced L929 cell necroptosis. However, RIP3 knockdown was shown to switch TNFα-induced necroptosis to apoptosis in L929 cells in other studies. Therefore, whether RIP3 knockdown blocks the TNFα-induced death of L929 cells is controversial.