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Keeping Cell Death in Check: Ubiquitylation-Dependent Control of TNFR1 and TLR Signaling

Laura Griewahn1,2,3, Aaron Köser1, Ulrich Maurer1,2,4

  • 1Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg im Breisgau, Germany.

Frontiers in Cell and Developmental Biology
|July 19, 2019
PubMed

Insights

Ubiquitylation regulates pro-inflammatory signaling pathways and gene expression. This process, controlled by ubiquitin ligases and deubiquitinases, also governs cell death thresholds induced by tumor necrosis factor receptor 1 (TNFR1) and toll-like receptors (TLRs).

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Pro-inflammatory signaling is crucial for immune responses, pathogen defense, and tissue repair.
  • Ubiquitylation, a post-translational modification, plays a critical role in regulating signaling pathways.
  • Receptor signaling complexes, including those for tumor necrosis factor receptor 1 (TNFR1) and toll-like receptors (TLRs), are key mediators of inflammation.

Purpose of the Study:

  • To review the pivotal role of ubiquitylation in TNFR1 and TLRs-mediated pro-inflammatory signaling.
  • To elucidate how ubiquitylation controls kinase activation and gene expression in response to inflammatory stimuli.
  • To discuss the involvement of ubiquitylation in regulating cell death thresholds triggered by these receptors.

Main Methods:

  • This review synthesizes existing literature on ubiquitylation in inflammation.
  • Key studies on ubiquitin ligases and deubiquitinases involved in TNFR1 and TLR signaling were analyzed.
  • Mechanisms linking ubiquitylation to kinase activation, gene expression, and cell death were examined.

Main Results:

  • Ubiquitylation of receptor signaling complex subunits is essential for initiating pro-inflammatory signaling.
  • Ubiquitylation controls the activation of kinases that drive pro-inflammatory gene expression.
  • Ubiquitylation critically regulates the balance between pro-survival and pro-death signaling downstream of TNFR1 and TLRs.

Conclusions:

  • Ubiquitylation is a central regulatory mechanism in TNFR1 and TLRs-mediated inflammation.
  • Understanding ubiquitylation dynamics is key to deciphering inflammatory responses and cell fate decisions.
  • Targeting ubiquitylation pathways may offer therapeutic strategies for inflammatory diseases.
Keywords:
TLRTNFTNFR1apoptosisinflammationnecroptosisubiquitin

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