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.
Highlights
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF superfamily ligands
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that induces apoptosis or necroptosis depending on cell conditions (Vasilikos et al, 2017)
It is important to note that RIPK3 is not expressed in most cancer cell lines due to methylation-dependent regulations, HaCat cells were described to be sensitive to TzB-induced necroptosis (Karl et al, 2014)
Summary
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF superfamily ligands. TRAIL binds to death receptors DR4 and DR5, resulting in the formation of a death inducing signaling complex leading to caspase−8 or −10 activation and apoptosis (Zamaraev et al, 2014). In a comparable way to TNFinduced necroptosis signaling (Vanden Berghe et al, 2014), necroptosis initiated by TRAIL is characterized by the formation of a stable cytosolic complex termed necrosome, which includes at least receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1 and RIPK3), mixed lineage kinase domain-like pseudokinase (MLKL), Fas-associated with death domain protein (FADD) and caspase-8. An important number of cancer cells remains resistant to TRAIL-induced death, due to high expression of anti-apoptotic factors (Newsom-Davis et al, 2009), such as inhibitors of apoptosis proteins (IAPs) (Vasilikos et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
