Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex

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Title
Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex
Author(s)
Jinho Seo; D Seong; Y W Nam; C H Hwang; S R Lee; C S Lee; Y Jin; H W Lee; Doo-Byoung Oh; P Vandenabeele; J Song
Bibliographic Citation
Cell Death and Differentiation, vol. 27, no. 9, pp. 3065-3081
Publication Year
2020
Abstract
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.
ISSN
1350-9047
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41418-020-0561-9
Type
Article
Appears in Collections:
Aging Convergence Research Center > 1. Journal Articles
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