TRIM21, a new component of the TRAIL-induced endogenous necrosome complex

Eugénio, Mélanie Simoes, Faurez, Florence, Kara-Ali, Ghania H., Lagarrigue, Mélanie, Uhart, Perrine, Bonnet, Marion C. ORCID: https://orcid.org/0000-0002-7559-2413, Gallais, Isabelle, Com, Emmanuelle, Pineau, Charles, Samson, Michel, Le Seyec, Jacques and Diamanche-Boitrel, Marie-Thérèse 2021. TRIM21, a new component of the TRAIL-induced endogenous necrosome complex. Frontiers in Molecular Biosciences 8 , 645134. 10.3389/fmolb.2021.645134

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a well-known apoptosis inducer and a potential anticancer agent. When caspases and inhibitors of apoptosis proteins (IAPs) are inhibited, TRAIL induces necroptosis. Molecular mechanisms of necroptosis rely on kinase activation, and on the formation of a necrosome complex, bringing together the receptor-interacting protein kinases 1 and 3 (RIPK1, RIPK3), and the mixed lineage kinase domain-like protein (MLKL). In this study, mass spectrometry approach allowed to identify the tripartite motif containing 21 (TRIM21), an E3 ubiquitin-protein ligase as a new partner of the endogenous TRAIL-induced necrosome. Alteration of TRIM21 expression level, obtained by transient transfection of HT29 or HaCat cells with TRIM21-targeted siRNAs or cDNA plasmids coding for TRIM21 demonstrated that TRIM21 is a positive regulator of TRAIL-induced necroptosis. Furthermore, the invalidation of TRIM21 expression in HT29 cells by CRISPR-Cas9 technology also decreased cell sensitivity to TRAIL-induced necroptosis, a shortcoming associated with a reduction in MLKL phosphorylation, the necroptosis executioner. Thus, TRIM21 emerged as a new partner of the TRAIL-induced necrosome that positively regulates the necroptosis process.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Frontiers Media
ISSN:	2296-889X
Date of First Compliant Deposit:	15 April 2021
Date of Acceptance:	17 February 2021
Last Modified:	05 May 2023 02:59
URI:	https://orca.cardiff.ac.uk/id/eprint/140497

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