Ppm1b negatively regulates necroptosis through dephosphorylating Rip3

Nat Cell Biol. 2015 Apr;17(4):434-44. doi: 10.1038/ncb3120. Epub 2015 Mar 9.


The auto-phosphorylation of murine receptor-interacting protein 3 (Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how Rip3 phosphorylation is regulated is still largely unknown. Here we identified protein phosphatase 1B (Ppm1b) as a Rip3 phosphatase and found that Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by Rip3 auto-phosphorylation in resting cells, and tumour necrosis factor-α (TNF)-induced necroptosis in cultured cells. We revealed that Ppm1b selectively suppresses necroptosis through the dephosphorylation of Rip3, which then prevents the recruitment of mixed lineage kinase domain-like protein (Mlkl) to the necrosome. We further showed that Ppm1b deficiency (Ppm1b(d/d)) in mice enhanced TNF-induced death in a Rip3-dependent manner, and the role of Ppm1b in inhibiting necroptosis was evidenced by elevated Rip3 phosphorylation and tissue damage in the caecum of TNF-treated Ppm1b(d/d) mice. These data indicate that Ppm1b negatively regulates necroptosis through dephosphorylating Rip3 in vitro and in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Apoptosis / genetics*
  • Cecum / cytology
  • Cell Line
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoprotein Phosphatases / genetics*
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Phosphatase 2C
  • RNA Interference
  • RNA, Small Interfering
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha


  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • MLKL protein, mouse
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • PPM1B protein, human
  • Phosphoprotein Phosphatases
  • Ppm1b protein, mouse
  • Protein Phosphatase 2C