Ppm1b negatively regulates necroptosis through dephosphorylating Rip3.

Nature cell biology 2015 Apr

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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.

Citation

Wanze Chen, Jianfeng Wu, Lisheng Li, Zhengmao Zhang, Junming Ren, Yaoji Liang, Fenfang Chen, Chao Yang, Zhenru Zhou, Sheng Sean Su, Xinru Zheng, Zhirong Zhang, Chuan-Qi Zhong, Haoqiang Wan, Mu Xiao, Xia Lin, Xin-Hua Feng, Jiahuai Han. Ppm1b negatively regulates necroptosis through dephosphorylating Rip3. Nature cell biology. 2015 Apr;17(4):434-44