Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

By Xin Chen, Wenjuan Li, Junming Ren, Deli Huang, Wan-ting He, Yunlong Song, Chao Yang, Wanyun Li, Xinru Zheng, Pengda Chen and 1 more. Cell Research, 2013

749 citations recorded by the source corpus.

Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain (HBD*) triggers necroptosis. Notably, forcing together the N-terminal domain (ND) but not the C-terminal kinase domain of MLKL causes necroptosis. Further deletion analysis showed that the four-α-helix bundle of MLKL (1-130 amino acids) is sufficient to trigger necroptosis. Both the HBD*-mediated and TNF-induced complexes of MLKL(ND) or MLKL are tetramers, and translocation of these complexes to lipid rafts of the plasma membrane precedes cell death. The homo-oligomerization is required for MLKL translocation and the signal sequence for plasma membrane location is located in the junction of the first and second α-helices of MLKL. The plasma membrane translocation of MLKL or MLKL(ND) leads to sodium influx, and depletion of sodium from the cell culture medium inhibits necroptosis. All of the above phenomena were not seen in apoptosis. Thus, the MLKL oligomerization leads to translocation of MLKL to lipid rafts of plasma membrane, and the plasma membrane MLKL complex acts either by itself or via other proteins to increase the sodium influx, which increases osmotic pressure, eventually leading to membrane rupture.

Subfields: Immunology, Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/46e55404d6bb7e0a61c0f48f000f0ef273074cc0

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Citations in the corpus

Interrelation of Oxidative Stress and Inflammation in Neurodegenerative Disease: Role of TNF (2015, background): “Although it was initially suggested that RIP3mediated phosphorylation of MLKL causes necroptosis due to mitochondrial dysfunction, recent evidence shows that translocation of MLKL to the plasma membrane is required for TNF-induced necroptosis [135, 136].”
Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. (2014, background): “The result that oligomerizedMLKL directly disruptsmembrane bilayer by forming pores also reconciled the conflicting reports that calcium or sodium influx into cells is required for necroptosis execution (Cai et al., 2014; Chen et al., 2014).”
GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death (2016, neutral): “Alternatively, it has been also proposed that plasma membrane-bound MLKL recruits Ca 2+ or Na + ion channels to permeabilize the membrane (Cai et al , 2014; Chen et al , 2014).”
Necroptosis: Mechanisms and Relevance to Disease (2016, neutral): “The exact stoichiometry of MLKL oligomers has not been clarified yet (16, 17), but it seems that MLKL oligomerization and/or its translocation to the plasma membrane relies on the cytosolic chaperone heat shock protein 90kDa alpha family class A member 1 (HSP90AA1; best known as HSP90) (22–24).”
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 (2014, background): “specific phospholipids, resulting in the loss of barrier function.(170,171,174,175,188) Recent data argue against an essential role for mitochondria in necroptosis.”