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Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis

Kathrin Weber (UGent) , Ria Roelandt (UGent) , Inge Bruggeman (UGent) , Yann Estornes (UGent) and Peter Vandenabeele (UGent)
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Abstract
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.
Keywords
MIXED LINEAGE KINASE, INTERACTING PROTEIN-3 RIP3, KAPPA-B ACTIVATION, CELL-DEATH, PROGRAMMED NECROSIS, NLRP3 INFLAMMASOME, RECEPTOR, DOMAIN, APOPTOSIS, BINDING

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Citation

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Chicago
Weber, Kathrin, Ria Roelandt, Inge Bruggeman, Yann Estornes, and Peter Vandenabeele. 2018. “Nuclear RIPK3 and MLKL Contribute to Cytosolic Necrosome Formation and Necroptosis.” Communications Biology 1.
APA
Weber, K., Roelandt, R., Bruggeman, I., Estornes, Y., & Vandenabeele, P. (2018). Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis. COMMUNICATIONS BIOLOGY, 1.
Vancouver
1.
Weber K, Roelandt R, Bruggeman I, Estornes Y, Vandenabeele P. Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis. COMMUNICATIONS BIOLOGY. 2018;1.
MLA
Weber, Kathrin et al. “Nuclear RIPK3 and MLKL Contribute to Cytosolic Necrosome Formation and Necroptosis.” COMMUNICATIONS BIOLOGY 1 (2018): n. pag. Print.
@article{8610675,
  abstract     = {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.},
  articleno    = {6},
  author       = {Weber, Kathrin and Roelandt, Ria and Bruggeman, Inge and Estornes, Yann and Vandenabeele, Peter},
  issn         = {2399-3642},
  journal      = {COMMUNICATIONS BIOLOGY},
  keywords     = {MIXED LINEAGE KINASE,INTERACTING PROTEIN-3 RIP3,KAPPA-B ACTIVATION,CELL-DEATH,PROGRAMMED NECROSIS,NLRP3 INFLAMMASOME,RECEPTOR,DOMAIN,APOPTOSIS,BINDING},
  language     = {eng},
  pages        = {13},
  title        = {Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis},
  url          = {http://dx.doi.org/10.1038/s42003-017-0007-1},
  volume       = {1},
  year         = {2018},
}

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