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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 (UGent) , et al.
(2020) CELL DEATH AND DIFFERENTIATION. 27(11). p.3065-3081
Author
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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 TNF alpha, 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.
Keywords
MIXED LINEAGE KINASE, DOMAIN-LIKE PROTEIN, PROGRAMMED NECROSIS, CELL-DEATH, NECROPTOSIS, RIP3, PHOSPHORYLATION, APOPTOSIS, UBIQUITINATION, INFLAMMATION

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MLA
Seo, Jinho, et al. “Beclin 1 Functions as a Negative Modulator of MLKL Oligomerisation by Integrating into the Necrosome Complex.” CELL DEATH AND DIFFERENTIATION, vol. 27, no. 11, 2020, pp. 3065–81, doi:10.1038/s41418-020-0561-9.
APA
Seo, J., Seong, D., Nam, Y. W., Hwang, C. H., Lee, S. R., Lee, C.-S., … Song, J. (2020). Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex. CELL DEATH AND DIFFERENTIATION, 27(11), 3065–3081. https://doi.org/10.1038/s41418-020-0561-9
Chicago author-date
Seo, Jinho, Daehyeon Seong, Young Woo Nam, Chi Hyun Hwang, Seung Ri Lee, Choong-Sil Lee, Young Jin, et al. 2020. “Beclin 1 Functions as a Negative Modulator of MLKL Oligomerisation by Integrating into the Necrosome Complex.” CELL DEATH AND DIFFERENTIATION 27 (11): 3065–81. https://doi.org/10.1038/s41418-020-0561-9.
Chicago author-date (all authors)
Seo, Jinho, Daehyeon Seong, Young Woo Nam, Chi Hyun Hwang, Seung Ri Lee, Choong-Sil Lee, Young Jin, Han-Woong Lee, Doo-Byoung Oh, Peter Vandenabeele, and Jaewhan Song. 2020. “Beclin 1 Functions as a Negative Modulator of MLKL Oligomerisation by Integrating into the Necrosome Complex.” CELL DEATH AND DIFFERENTIATION 27 (11): 3065–3081. doi:10.1038/s41418-020-0561-9.
Vancouver
1.
Seo J, Seong D, Nam YW, Hwang CH, Lee SR, Lee C-S, et al. Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex. CELL DEATH AND DIFFERENTIATION. 2020;27(11):3065–81.
IEEE
[1]
J. Seo et al., “Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex,” CELL DEATH AND DIFFERENTIATION, vol. 27, no. 11, pp. 3065–3081, 2020.
@article{8707536,
  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 TNF alpha, 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.}},
  author       = {{Seo, Jinho and Seong, Daehyeon and Nam, Young Woo and Hwang, Chi Hyun and Lee, Seung Ri and Lee, Choong-Sil and Jin, Young and Lee, Han-Woong and Oh, Doo-Byoung and Vandenabeele, Peter and Song, Jaewhan}},
  issn         = {{1350-9047}},
  journal      = {{CELL DEATH AND DIFFERENTIATION}},
  keywords     = {{MIXED LINEAGE KINASE,DOMAIN-LIKE PROTEIN,PROGRAMMED NECROSIS,CELL-DEATH,NECROPTOSIS,RIP3,PHOSPHORYLATION,APOPTOSIS,UBIQUITINATION,INFLAMMATION}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{3065--3081}},
  title        = {{Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex}},
  url          = {{http://doi.org/10.1038/s41418-020-0561-9}},
  volume       = {{27}},
  year         = {{2020}},
}
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