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Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis.
Weber, Kathrin; Roelandt, Ria; Bruggeman, Inge; Estornes, Yann; Vandenabeele, Peter.
Afiliação
  • Weber K; VIB Inflammation Research Center, Technologiepark 927, 9052, Zwijnaarde-Ghent, Belgium. k.w.e@gmx.de.
  • Roelandt R; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052, Zwijnaarde-Ghent, Belgium. k.w.e@gmx.de.
  • Bruggeman I; VIB Inflammation Research Center, Technologiepark 927, 9052, Zwijnaarde-Ghent, Belgium.
  • Estornes Y; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052, Zwijnaarde-Ghent, Belgium.
  • Vandenabeele P; VIB Inflammation Research Center, Technologiepark 927, 9052, Zwijnaarde-Ghent, Belgium.
Commun Biol ; 1: 6, 2018.
Article em En | MEDLINE | ID: mdl-30271893
Necroptotic signaling converges in the assembly of a cytosolic signaling platform, the necrosome, with the activation of its downstream effector, MLKL. RIPK1 and RIPK3, key components of the necrosome, act as signaling intermediates for the activation of MLKL. We report that RIPK3 and MLKL continuously shuttle between the nucleus and the cytoplasm, whereas RIPK1 is constitutively present in both compartments. During TNF-induced necroptosis, nuclear RIPK1 becomes ubiquitinated, after which nuclear MLKL becomes phosphorylated and oligomerized. Pharmacological inhibition of the nuclear export machinery leads to retention of RIPK3 and MLKL in the nucleus, prevents the nucleation of cytosolic RIPK3/MLKL oligomerization, and reduces cell death. Our results suggest that passage of necroptotic signaling components through the nucleus is a mechanism for regulating cytosolic necrosome formation and consequently necroptotic cell death.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2018 Tipo de documento: Article