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Ppm1b negatively regulates necroptosis through dephosphorylating Rip3

Wanze Chen1, Jianfeng Wu1, Lisheng Li1

  • 1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.

Nature Cell Biology
|March 10, 2015
PubMed

Insights

Protein phosphatase 1B (Ppm1b) dephosphorylates receptor-interacting protein 3 (Rip3), restricting programmed cell death (necroptosis). Ppm1b deficiency enhances necroptosis, highlighting its inhibitory role.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Receptor-interacting protein 3 (Rip3) auto-phosphorylation is crucial for necroptosis initiation.
  • Regulation of Rip3 phosphorylation remains largely uncharacterized.
  • Necroptosis is a key form of programmed cell death with implications in disease.

Purpose of the Study:

  • To identify regulators of Rip3 phosphorylation.
  • To investigate the role of protein phosphatase 1B (Ppm1b) in necroptosis.
  • To elucidate the mechanism by which Ppm1b controls necroptosis.

Main Methods:

  • Biochemical assays to identify Rip3 phosphatase activity.
  • In vitro and in vivo studies using cell cultures and mouse models.
  • Analysis of Rip3 phosphorylation status and mixed lineage kinase domain-like protein (Mlkl) recruitment.

Main Results:

  • Protein phosphatase 1B (Ppm1b) was identified as a Rip3 phosphatase.
  • Ppm1b restricts both spontaneous and TNF-induced necroptosis.
  • Ppm1b dephosphorylates Rip3, preventing Mlkl recruitment and subsequent necroptosis.
  • Ppm1b deficiency exacerbates TNF-induced necroptosis and tissue damage in mice.

Conclusions:

  • Ppm1b acts as a negative regulator of necroptosis.
  • Ppm1b selectively suppresses necroptosis by dephosphorylating Rip3.
  • Targeting Ppm1b may offer therapeutic strategies for necroptosis-related conditions.

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