Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1's Cytotoxic Potential.
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ICR Authors
Authors
Feltham, R
Jamal, K
Tenev, T
Liccardi, G
Jaco, I
Domingues, CM
Morris, O
John, SW
Annibaldi, A
Widya, M
Kearney, CJ
Clancy, D
Elliott, PR
Glatter, T
Qiao, Q
Thompson, AJ
Nesvizhskii, A
Schmidt, A
Komander, D
Wu, H
Martin, S
Meier, P
Jamal, K
Tenev, T
Liccardi, G
Jaco, I
Domingues, CM
Morris, O
John, SW
Annibaldi, A
Widya, M
Kearney, CJ
Clancy, D
Elliott, PR
Glatter, T
Qiao, Q
Thompson, AJ
Nesvizhskii, A
Schmidt, A
Komander, D
Wu, H
Martin, S
Meier, P
Document Type
Journal Article
Date
2018-04-10
Date Accepted
2018-03-13
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 association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2's E3 activity or RIPK1's ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF.
Citation
Cell reports, 2018, 23 (2), pp. 470 - 484
Source Title
Publisher
CELL PRESS
ISSN
2211-1247
eISSN
2211-1247
Collections
Research Team
Cell Death and Immunity
Target Discovery & Apoptosis
Target Discovery & Apoptosis