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TRIM21, a New Component of the TRAIL-Induced Endogenous Necrosome Complex

Mélanie Simoes Eugénio1, Florence Faurez1, Ghania H Kara-Ali1

  • 1Univ-Rennes1, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S1085, Rennes, France.

Frontiers in Molecular Biosciences
|May 3, 2021
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers necroptosis, a cell death pathway. This study identifies tripartite motif containing 21 (TRIM21) as a key positive regulator of TRAIL-induced necroptosis.

Area of Science:

  • Cellular and Molecular Biology
  • Immunology
  • Cancer Research

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis and has anticancer potential.
  • TRAIL can induce necroptosis, a programmed form of necrosis, under specific conditions (e.g., caspase inhibition).
  • Necroptosis involves kinase activation and the formation of a necrosome complex including RIPK1, RIPK3, and MLKL.

Purpose of the Study:

  • To identify novel protein partners of the TRAIL-induced necrosome.
  • To investigate the role of tripartite motif containing 21 (TRIM21) in TRAIL-induced necroptosis.

Main Methods:

  • Mass spectrometry was employed to identify proteins interacting with the TRAIL-induced necrosome.
  • Functional studies involved altering TRIM21 expression using siRNAs, cDNA plasmids, and CRISPR-Cas9 gene editing in HT29 and HaCat cells.
  • MLKL phosphorylation levels were assessed to evaluate necroptosis execution.

Main Results:

  • Tripartite motif containing 21 (TRIM21), an E3 ubiquitin-protein ligase, was identified as a novel component of the endogenous TRAIL-induced necrosome.
  • Altering TRIM21 expression levels (up or down) modulated cellular sensitivity to TRAIL-induced necroptosis.
  • CRISPR-Cas9-mediated invalidation of TRIM21 reduced sensitivity to TRAIL-induced necroptosis, correlating with decreased MLKL phosphorylation.

Conclusions:

  • TRIM21 is a newly discovered partner of the TRAIL-induced necrosome.
  • TRIM21 acts as a positive regulator of TRAIL-induced necroptosis.
  • TRIM21 influences the necroptosis pathway by affecting MLKL phosphorylation.
Keywords:
TRAILTRIM21necroptosisnecrosomeproteomics

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