TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL

Ayaz Najafov, Adnan K. Mookhtiar, Hoang Son Luu, A. Ordureau, Heling Pan, Palak P. Amin, Ying Li, Qingxian Lu, Junying Yuan

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Necroptosis, a cell death pathway mediated by the RIPK1-RIPK3-MLKL signaling cascade downstream of tumor necrosis factor α (TNF-α), has been implicated in many inflammatory diseases. Members of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases are known for their anti-apoptotic, oncogenic, and anti-inflammatory roles. Here, we identify an unexpected role of TAM kinases as promoters of necroptosis, a pro-inflammatory necrotic cell death. Pharmacologic or genetic targeting of TAM kinases results in a potent inhibition of necroptotic death in various cellular models. We identify phosphorylation of MLKL Tyr376 as a direct point of input from TAM kinases into the necroptosis signaling. The oligomerization of MLKL, but not its membranal translocation or phosphorylation by RIPK3, is controlled by TAM kinases. Importantly, both knockout and inhibition of TAM kinases protect mice from systemic inflammatory response syndrome. In conclusion, this study discovers that immunosuppressant TAM kinases are promoters of pro-inflammatory necroptosis, shedding light on the biological complexity of the regulation of inflammation. TAM kinases are known for their oncogenic, anti-apoptotic, and anti-inflammatory roles. Najafov et al. discover an unexpected role for TAM kinases in mediating necroptosis, a pro-inflammatory programmed necrotic cell death. Mechanistic studies reveal that TAM kinases phosphorylate MLKL and promote its oligomerization, a step that forms a cell-membrane-rupturing pore.

Original languageEnglish (US)
Pages (from-to)457-468.e4
JournalMolecular cell
Volume75
Issue number3
DOIs
StatePublished - Aug 8 2019
Externally publishedYes

Keywords

  • Axl
  • cell death
  • Mer
  • MLKL
  • necroptosis
  • TAM kinases
  • Tyro3

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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