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Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis
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Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis

Published on: November 14, 2025

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Necroptosis is preceded by nuclear translocation of the signaling proteins that induce it

S Yoon1, K Bogdanov1, A Kovalenko1

  • 1Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.

Cell Death and Differentiation
|July 18, 2015
PubMed

Insights

Programmed necrotic cell death (necroptosis) involves RIPK1, RIPK3, and MLKL proteins. This study reveals that phosphorylated MLKL, RIPK1, and RIPK3 translocate to the nucleus before MLKL binds cell membranes to trigger necroptosis.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Immunology

Background:

  • Programmed necrotic cell death (necroptosis) is a crucial cellular process activated by cytokines and pathogen components.
  • Key proteins in necroptosis include RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL).
  • The precise sequence of events and subcellular localization during MLKL activation remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular events and subcellular localization preceding MLKL activation during necroptosis.
  • To investigate the role of nuclear translocation in the necroptosis signaling pathway.

Main Methods:

  • Cellular assays to track protein localization.
  • Phosphorylation-specific antibodies to detect activated MLKL.
  • Confocal microscopy to visualize protein translocation.

Main Results:

  • Phosphorylated MLKL, RIPK1, and RIPK3 were observed to translocate to the nucleus.
  • This nuclear translocation precedes the association of MLKL with cellular membranes.
  • These findings suggest a nuclear role in the initiation of the necroptosis pathway.

Conclusions:

  • The study identifies nuclear translocation of key necroptosis proteins as a critical early event.
  • This nuclear phase precedes the membrane-binding and ion-flux activities of MLKL.
  • These findings refine our understanding of the necroptosis signaling cascade and MLKL activation.

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