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

Shuo Yang, Bingwei Wang, Lisa S. Tang, Jakub Siednienko, John J. Callanan and Paul N. Moynagh ()
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Shuo Yang: Institute of Immunology, National University of Ireland Maynooth
Bingwei Wang: Institute of Immunology, National University of Ireland Maynooth
Lisa S. Tang: Institute of Immunology, National University of Ireland Maynooth
Jakub Siednienko: Institute of Immunology, National University of Ireland Maynooth
John J. Callanan: UCD School of Veterinary Medicine, Conway Institute of Biomolecular and Biomedical Research, UCD
Paul N. Moynagh: Institute of Immunology, National University of Ireland Maynooth

Nature Communications, 2013, vol. 4, issue 1, 1-19

Abstract: Abstract Tumour necrosis factor-α (TNF) can activate NF-κB 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-κB 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.

Date: 2013
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DOI: 10.1038/ncomms3583

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