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Plasma membrane translocation of trimerized Mixed Lineage Kinase Domain-like protein (MLKL) is requisite for TNF-induced necrosis

Thursday, November 07, 2013 — Poster Session II

12:00 p.m. – 2:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • Z Cai
  • S Jitkaew
  • J Zhao
  • H Chiang
  • S Choksi
  • Y Ward
  • L Wu
  • Z Liu


The mixed lineage kinase domain-like protein, MLKL, has been recently identified as a key RIP3 downstream component of TNF-induced necrosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necrosis. Here, we report that MLKL forms a homotrimer through its N-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necrosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL are critical for mediating necrosis. Importantly, we found that the membrane localization of MLKL is essential for Ca2+ influx, which is an early event of TNF-induced necrosis. Furthermore, we identified that transient receptor potential melastatin related 7 (TRPM7) is a MLKL downstream target for the mediation of Ca2+ influx and TNF-induced necrosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necrosis.

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