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

Melanie Simoes Eugenio (1, 2) , Florence Faurez (1, 2) , Ghania H. Kara-Ali (1, 2) , Mélanie Lagarrigue (1, 3) , Perrine Uhart (1, 2) , Marion C. Bonnet (1, 2) , Isabelle Gallais (1, 2) , Emmanuelle Com (1, 3) , Charles Pineau (1, 3) , Michel Samson (1, 2) , Jacques Le Seyec (1, 2) , Marie-Thérèse Dimanche-Boitrel (1, 2)

1 Irset - Institut de recherche en santé, environnement et travail
2 EHESP - École des Hautes Études en Santé Publique [EHESP]
3 Plateforme Génomique Santé Biogenouest®

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.

Mots clés: TRIM21; necroptosis; TRAIL; necrosome; proteomics

Domaines: Sciences du Vivant [q-bio]

Melanie Simoes Eugenio, Florence Faurez, Ghania H. Kara-Ali, Mélanie Lagarrigue, Perrine Uhart, et al.. TRIM21, a New Component of the TRAIL-Induced Endogenous Necrosome Complex. Frontiers in Molecular Biosciences, 2021, 8, ⟨10.3389/fmolb.2021.645134⟩. ⟨hal-03244958v2⟩