Necroptosis is a form of regulated cell death caused by formation of the necrosome complex. However, the factors modulating this process and the systemic pathophysiological effects of necroptosis are yet to be understood. Here, we identified that Beclin 1 functions as an anti-necroptosis factor by being recruited into the necrosome complex upon treatment with TNFα, Smac mimetic, and pan-caspase inhibitor and by repressing MLKL oligomerisation, thus preventing the disruption of the plasma membrane. Cells ablated or knocked-out for Beclin 1 become sensitised to necroptosis in an autophagy-independent manner without affecting the necrosome formation itself. Interestingly, the recruitment of Beclin 1 into the necrosome complex is dependent on the activation and phosphorylation of MLKL. Biochemically, the coiled-coil domain (CCD) of Beclin 1 binds to the CCD of MLKL, which restrains the oligomerisation of phosphorylated MLKL. Finally, Beclin 1 depletion was found to promote necroptosis in leukaemia cells and enhance regression of xenografted-tumour upon treatment with Smac mimetics and caspase inhibitors. These results suggest that Beclin 1 functions as a negative regulator in the execution of necroptosis by suppressing MLKL oligomerisation.
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Acknowledgements We thank Myung-Shik Lee for LyzMCre mice. This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2015R1A3A2066581) (to JSong) and by Basic Science Research Program through the NRF funded by the Ministry of Education (2017R1A6A3A11035262) (to JSeo). This work was supported in part by Brain Korea 21 (BK21) PLUS program and JSeo, DS, and YWN are fellowship awardee by BK21 PLUS program (to JSeo, DS, and YWN). Additionally, This research was partly supported by Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (to JSeo). PV is a senior full professor at Ghent University and senior PI at the VIB Center for Inflammation Research (IRC). His research is supported by Belgian grants (EOS 30826052 MODEL-IDI), Flemish grants (Research Foundation Flanders: FWO G.0C31.14N, FWO G.0C37.14N, FWO G0E04.16N, G.0C76.18N, G.0B71.18N), grants from Ghent University (BOF16/MET_V/007 Methusalem grant) ‘Foundation against Cancer, (FAF-F/2016/865) and VIB.
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology