Journal article

Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1's Cytotoxic Potential

Rebecca Feltham, Kunzah Jamal, Tencho Tenev, Gianmaria Liccardi, Isabel Jaco, Celia Monteiro Domingues, Otto Morris, Sidonie Wicky John, Alessandro Annibaldi, Marcella Widya, Conor J Kearney, Danielle Clancy, Paul R Elliott, Timo Glatter, Qi Qiao, Andrew J Thompson, Alexey Nesvizhskii, Alexander Schmidt, David Komander, Hao Wu Show all

Cell Reports | CELL PRESS | Published : 2018

Abstract

Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD ..

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Grants

Awarded by Breast Cancer Now


Awarded by Medical Research Council (MRC)


Awarded by Komen Promise


Awarded by Worldwide Cancer Research


Awarded by Biotechnology and Biological Sciences Research (BBSRC)


Awarded by Cancer Research UK (CRUK)


Awarded by Science Foundation Ireland


Awarded by Irish Research Council for Science Engineering and Technology (IRCSET) postgraduate studentship


Awarded by NIH


Awarded by MRC


Awarded by European Research Council


Funding Acknowledgements

We would like to thank Henning Walczak, Freddy Radtke, Shaomeng Wang, Patricia J. Gallagher, Vanessa Redecke, Katrin Rittinger, and Ivan Dikic for reagents and advice. We also thank members of the Komander and Meier labs for helpful discussions. We would like to apologize to the many authors whose work we could not cite because of space restrictions. Work in the Meier lab is funded by Breast Cancer Now (CTR-QR14-007), the Medical Research Council (MRC) (MR/M019217/1), Komen Promise (PG12220321), Worldwide Cancer Research (15-0042), Biotechnology and Biological Sciences Research (BBSRC) (BB/L021684/1), and postgraduate studentships from Cancer Research UK (CRUK) (CRM089X). The Martin laboratory is supported by PI (08/IN.1/B2031) and SRC (07/SRC/B1144) grants from Science Foundation Ireland. C.J.K. was supported by an Irish Research Council for Science Engineering and Technology (IRCSET) postgraduate studentship (RS/2010/2542). The Nesvizhskii lab is supported by the NIH (GM094231 and CA126239). The Wu lab is funded by the NIH (AI050872 to H.W.). Work in the Komander lab is funded by the MRC (U105192732), the European Research Council (724804), and the Lister Institute of Preventive Medicine. We acknowledge National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre.