MLKL binds PIPs

Stable Identifier
Reaction [binding]
Homo sapiens
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Activated by phosphorylation mixed lineage kinase domain-like protein (MLKL) was found to translocate to lipid rafts of the plasma membrane, where MLKL interacts with phosphatidylinositol phosphates (PIPs) via a patch of positively charged amino acids at the surface of a four-helical bundle domain (4HBD) located in its N-terminal region (Dondelinger Y et al. 2014; Wang H et al. 2014). Interfering with the formation of PI(5)P or PI(4,5)P2 using PIP inhibitors (such as PIKfyve (P5i)) efficiently inhibited TNFalpha-induced necroptosis in both mouse L929 and the human FADD-null Jurkat cells (Dondelinger Y et al. 2014). In vitro liposome experiments revealed that MLKL has induced leakage of PIP- or cardiolipin-containing liposomes suggesting that MLKL may have pore-forming capacities to mediate cell death by permeabilizing PIP- or cardiolipin-containing membranes (Dondelinger Y et al. 2014; Wang H et al. 2014). Other study showed that translocation of MLKL to plasma membrane following necroptosis induction in human colon adenocarcinoma HT29 and FADD-null Jurkat cells is associated with Ca2+ influx. MLKL-mediated calcium influx was completely blocked in MLKL-knockdown by shRNA HT29 cells and upon treatment with MLKL chemical inhibitor necrosulfonamide (NSA) (Cai Z et al. 2014). Thus, proposed MLKL functions are (1) binding to and creating pores on the plasma membrane surface and/or (2) regulating ion influx through channels and disturbing the osmotic homeostasis of the cell. Both scenarios lead to the typical cell swelling (“oncosis”) associated with necroptosis.

Literature References
PubMed ID Title Journal Year
24813885 MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates

Dondelinger, Y, Declercq, W, Montessuit, S, Roelandt, R, Goncalves, A, Bruggeman, I, Hulpiau, P, Weber, K, Sehon, CA, Marquis, RW, Bertin, J, Gough, PJ, Savvides, S, Martinou, JC, Bertrand, MJ, Vandenabeele, P

Cell Rep 2014
24316671 Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

Cai, Z, Jitkaew, S, Zhao, J, Chiang, HC, Choksi, S, Liu, J, Ward, Y, Wu, LG, Liu, ZG

Nat. Cell Biol. 2014
24703947 Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3

Wang, H, Sun, L, Su, L, Rizo, J, Liu, L, Wang, LF, Wang, FS, Wang, X

Mol. Cell 2014
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