Ppm1b negatively regulates necroptosis through dephosphorylating Rip3.
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.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Wanze
W
Chen
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Jianfeng
J
Wu
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Lisheng
L
Li
1] Life Sciences Institute, and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Zhengmao
Z
Zhang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Junming
J
Ren
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Yaoji
Y
Liang
Life Sciences Institute, and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Fenfang
F
Chen
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Chao
C
Yang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Zhenru
Z
Zhou
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Sheng Sean
SS
Su
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Xinru
X
Zheng
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Zhirong
Z
Zhang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Chuan-Qi
CQ
Zhong
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Haoqiang
H
Wan
Life Sciences Institute, and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Mu
M
Xiao
Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Xia
X
Lin
1] Life Sciences Institute, and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China [2] Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Xin-Hua
XH
Feng
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
Jiahuai
J
Han
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002432:Cecum / Q000166:cytology; D002460:Cell Line; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D034622:RNA Interference; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha
D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C000607457:PPM1B protein, human; D010749:Phosphoprotein Phosphatases; C000607467:Ppm1b protein, mouse; D000071636:Protein Phosphatase 2C