Page 20 - G. Cell differentiation. division. and death

[G. Cell differentiation, division, and death-14]

Beclin1 suppresses TNF-α-induced necroptosis via inhibition

of MLKL oligomerization in necrosomes

Young Woo Nam¹˙#, Jinho Seo²˙#, Daehyeon Seong¹˙#, Jaewhan Song¹

¹Department of Biochemistry, College of Life science and Biotechnology, Yonsei University, Seoul 03722, Korea,

²Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB),
Daejeon 34141, Korea

Beclin1 is a key protein involved in mediating autophagy. When beclin1 is activated due to metabolic stress, it

dissociates from the beclin1-bcl-2 heterodimer, forming beclin1 monomer. Subsequently, the beclin1 monomer

forms the PI3K complex by interacting with Vps34, Vps15, and Atg14 to induce autophagy. In this study, we identified
another function of beclin1, and found that it is autophagy independent.

Necroptosis is a type of programmed cell death and, TNF-α-induced necroptosis is the most studied pathway of

necroptosis. In TNF-α-induced necroptosis, RIPK1 is activated by autophosphorylation. Phospho-RIPK1 subsequently
phosphorylates RIPK3, and activated phoshpo-RIPK3 in turn phosphorylates MLKL. The complex composed of RIPK1,

RIPK3, and MLKL is called the necrosome, and is a key complex involved in necroptosis. Phosphorylated MLKL forms
an oligomer and translocates into the plasma membrane. MLKL oligomer in the plasma membrane causes

membrane rupture. Moreover, upon necrosome formation, beclin1 is recruited into the necrosome and it interacts
with MLKL via a coiled-coil domain. Due to this interaction, beclin1 in the necrosome inhibits MLKL oligomerization

and consequently, necroptosis is suppressed.