Journal
FRONTIERS IN MOLECULAR BIOSCIENCES
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2021.645134
Keywords
TRIM21; necroptosis; TRAIL; necrosome; proteomics
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Funding
- National Institute for Cancer (INCa)
- Ligue Contre le Cancer (Ille et Vilaine Committee)
- National Institute of Health and Medical Research (Inserm)
- University of Rennes 1
- Region Bretagne
- Contrat de Plan Etat-Region (CPER) grant named Infectio
- Fondation pour la Recherche Medicale [DEQ20180339216]
- Biogenouest
- INCa
- European University of Brittany (Excellence Research Chair)
- Ligue Contre le Cancer (committee Ille et Vilaine)
- UFR Pharmacy of University of Rennes 1
- Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation
- Ligue Contre le Cancer (LoireAtlantique Committee)
- Ligue Contre le Cancer (Maine et Loire Committee)
- Conseil Regional de Bretagne
- Infrastructures en Biologie Sante et Agronomie (IBiSA)
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TRIM21 has been identified as a new partner of the TRAIL-induced necrosome, acting as a positive regulator of the necroptosis process.
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.
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