Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α

Abstract

Tumour necrosis factor-a (TNF) can activate NF-kB to induce pro-inflammatory genes but can also stimulate the caspase cascade to promote apoptosis. Here we show that deficiency of the ubiquitin E3 ligase, Pellino3, sensitizes cells to TNF-induced apoptosis without inhibiting the NF-kB pathway. Suppressed expression of Pellino3 leads to enhanced formation of the death-induced signalling complex, complex II, in response to TNF. We show that Pellino3 targets RIP1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation and caspase 8-mediated cleavage of RIP1 in response to TNF/cycloheximide co-stimulation. Pellino3-deficient mice also show increased sensitivity to TNF-induced apoptosis and greatly increased lethality in response to TNF administration. These findings define Pellino3 as a novel regulator of TNF signalling and an important determining factor in dictating whether TNF induces cell survival or death.

Autophagy-dependent PELI3 degradation inhibits proinflammatory IL1B expression

“…Sepsis is a disease with an initial overwhelming proinflammatory response due to infection and a delayed onset of immune paralysis with suppression of immune cells. 8 Based on previous studies, which characterized PELI3 as a scaffold protein and interacting partner of TRAF6, MAP3K7, NFKB-inducing kinase MAP3K14/NIK (mitogen-activated protein kinase kinase kinase 14), and IRAK1, our aim was to identify potent binding partners essential for LPS-regulated processes. 10,12 The discovery of SQSTM1 as a novel PELI3-binding partner by MS as well as by western blot and immunofluorescence analysis ( Fig.…”

“…10,11 So far, PELI3 is implicated as activator of MAPK14/p38a, MAPK8/JNK1-MAPK9/JNK2, and MAPK1/ERK2-MAPK3/ERK1 signaling cascades of TLR/ IL1R pathways. [12][13][14][15] Furthermore, PELI3 0 s really interesting new gene (RING) domain, responsible for its E3 ubiquitin ligase activity, is necessary for IRAK1 ubiquitination and therefore promotes signal transduction. 16 Interestingly, TLR signaling is also connected to autophagy-dependent processes by recruiting BECN1/Beclin1 (Beclin 1, autophagy related), one of the key factors in autophagosome formation.…”

RIP kinases: key decision makers in cell death and innate immunity

“…45 Recently, we have demonstrated that a member of the Pellino E3 ubiquitin ligase family, Pellino3, targets RIP1 and impairs Complex II formation in the TNF signalling pathway to suppress cell apoptosis. 52 The kinase activity of RIP1 is required for ripoptosome assembly and its downstream triggering of apoptosis. 49,51 Thus the ubiquitination and kinase activity status of RIP1 dictates whether TNF signalling goes down the road of inflammatory gene expression or the terminal path to cell death.…”

Molecular and physiological roles of Pellino E3 ubiquitin ligases in immunity

“…Early studies in the Pellino field had indicated a lack of role for Pellino1 and Pellino2 in TNF‐induced activation of NFκB , but we have recently demonstrated an important role for Pellino3 in controlling cell fate in response to TNF ( Fig. ).…”

“…Caspase8 can also cleave RIP1 to further augment TNF‐induced apoptosis. Interestingly, we have shown that loss or knockdown of Pellino3 expression sensitizes cells to TNF‐induced apoptosis without regulating activation of the NF‐κB pathway . Instead Pellino3 is cytoprotective by interacting, via its FHA domain, with RIP1 and blocking the interaction of the latter with FADD and caspase8 ( Fig.…”