@article{8639545,
  abstract     = {{The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-kappa B signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-kappa B-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-kappa B activation. Apart from acting as an NF-kappa B inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.}},
  articleno    = {{692}},
  author       = {{Priem, Dario and Devos, Michael and Druwé, Sarah and Martens, Arne and Slowicka, Karolina and Ting, Adrian T and Pasparakis, Manolis and Declercq, Wim and Vandenabeele, Peter and van Loo, Geert and Bertrand, Mathieu}},
  issn         = {{2041-4889}},
  journal      = {{CELL DEATH & DISEASE}},
  keywords     = {{NF-KAPPA-B,ACTIVATION,DEATH,PHOSPHORYLATION,POLYUBIQUITIN,INFLAMMATION,COMPLEX,BINDING,CHAINS,CYLD}},
  language     = {{eng}},
  pages        = {{16}},
  title        = {{A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms}},
  url          = {{http://doi.org/10.1038/s41419-019-1937-y}},
  volume       = {{10}},
  year         = {{2019}},
}

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