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

Jinho Seo, Daehyeon Seong, Young Woo Nam, Chi Hyun Hwang, Seung Ri Lee, Choong Sil Lee, Young Jin, Han Woong Lee, Doo Byoung Oh, Peter Vandenabeele, Jaewhan Song

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - 2020 Jan 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Seo, J., Seong, D., Nam, Y. W., Hwang, C. H., Lee, S. R., Lee, C. S., Jin, Y., Lee, H. W., Oh, D. B., Vandenabeele, P., & Song, J. (Accepted/In press). Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex. Cell Death and Differentiation. https://doi.org/10.1038/s41418-020-0561-9