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Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO
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Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO

Published on: December 28, 2019

NEMO inhibits programmed necrosis in an NFκB-independent manner by restraining RIP1

Marie Anne O'Donnell1, Hidenori Hase, Diana Legarda

  • 1Immunology Institute, Mount Sinai School of Medicine, New York, New York, United States of America. marie.a.odonnell@mssm.edu

Plos One
|August 1, 2012
PubMed

Insights

NFκB essential modifier (NEMO) prevents programmed necrosis by binding to ubiquitinated RIP1, independent of gene transcription. Loss of NEMO or blocked RIP1 ubiquitination triggers necrosis when caspases are inhibited.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor Necrosis Factor Receptor 1 (TNFR1) signaling can induce either cell survival or cell death pathways.
  • While apoptosis is mediated by caspases, some cells undergo programmed necrosis upon caspase inhibition.
  • The regulatory mechanisms controlling programmed necrosis, particularly inhibitory signals, remain poorly understood.

Purpose of the Study:

  • To investigate the role of NFκB essential modifier (NEMO) in regulating programmed necrosis.
  • To elucidate the mechanism by which NEMO inhibits TNF-induced necrosis.
  • To determine if NEMO's anti-necrotic function is dependent on NFκB transcriptional activity.

Main Methods:

  • Utilized T cells genetically deficient in NEMO.
  • Stimulated cells with TNF in the presence of caspase inhibitors.
  • Investigated the interaction between NEMO, RIP1, and ubiquitination.
  • Assessed the impact of NEMO deficiency and RIP1 ubiquitination status on cell death pathways.

Main Results:

  • T cells lacking NEMO exhibited hypersensitivity to TNF-induced programmed necrosis when caspases were inhibited.
  • NEMO's pro-survival activity against necrosis was independent of NFκB-mediated gene transcription.
  • NEMO directly inhibited necrosis by binding to ubiquitinated RIP1, preventing its engagement in the necrotic pathway.
  • Necrosis occurred in the absence of NEMO or when RIP1 ubiquitination was blocked.

Conclusions:

  • NEMO acts as a critical inhibitor of TNF-induced programmed necrosis.
  • NEMO's inhibitory function relies on its interaction with ubiquitinated RIP1, independent of NFκB transcription.
  • The recruitment of NEMO to ubiquitinated RIP1 is a crucial determinant in the TNFR1 signaling pathway, dictating cell fate towards survival or necrosis.

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