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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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Published on: July 25, 2019

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Cell fate decisions regulated by K63 ubiquitination of tumor necrosis factor receptor 1

Jürgen Fritsch1, Mario Stephan1, Vladimir Tchikov1

  • 1Institute of Immunology, Christian Albrechts University of Kiel, Kiel, Germany.

Molecular and Cellular Biology
|July 2, 2014
PubMed

Insights

Tumor necrosis factor receptor 1 (TNF-R1) signaling is regulated by RNF8-mediated ubiquitination. This early checkpoint controls cell death versus survival decisions, impacting inflammation and proliferation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Tumor necrosis factor receptor 1 (TNF-R1) signaling initiates diverse cellular responses, including inflammation, proliferation, and apoptosis.
  • The precise molecular mechanisms governing TNF-R1-mediated cell fate decisions remain incompletely understood.

Purpose of the Study:

  • To investigate the role of RNF8-mediated ubiquitination as an early regulatory checkpoint in TNF-R1 signaling.
  • To elucidate how TNF-R1 ubiquitination influences downstream signaling pathways and cellular outcomes.

Main Methods:

  • Utilized TNF stimulation and assessed TNF-R1 ubiquitination status.
  • Investigated the impact of RNF8 modulation on receptor internalization, signaling complex formation, and caspase activation.
  • Analyzed NF-κB activation and cell proliferation in RNF8-deficient cells.

Main Results:

  • RNF8 mediates K63 ubiquitination of TNF-R1, acting as an early molecular checkpoint.
  • Downregulation of RNF8 inhibited TNF-R1 ubiquitination, receptor internalization, death-inducing signaling complex recruitment, and caspase activation, thereby reducing apoptosis.
  • RNF8 deficiency enhanced cell growth and proliferation by allowing unimpeded TRADD, TRAF2, RIP1 recruitment and NF-κB activation.

Conclusions:

  • K63 ubiquitination of TNF-R1 by RNF8 is a critical regulatory event at the initial stage of TNF-R1 signaling.
  • This ubiquitination event dictates the balance between cell death and survival pathways.
  • RNF8-mediated ubiquitination represents a novel regulatory mechanism controlling TNF-R1 signaling outcomes.

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