Ppm1b negatively regulates necroptosis through dephosphorylating Rip3
Open accessAbstract
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.
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Major negative regulators of necrosome include STUB1, A20, PPM1B, and AURKA.
“Major negative regulators of the necrosome include: (1) STIP1 homology and U-box containing protein 1 (STUB1; also known as CHIP), which promotes RIPK1 and RIPK3 ubiquitination followed by lysosomal degradation [472, 473]; (2) A20, which inhibits necrosome assembly by deubiquitinating RIPK3 [473, 474]; (3) protein phosphatase, Mg2+/Mn2+ dependent 1B (PPM1B), which prevents MLKL recruitment to the”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [475]
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- Authors
- Chen, W., Wu, J., Li, L., Zhang, Z., Ren, J., Liang, Y., Chen, F., Yang, C., Zhou, Z., Sean Su, S., Zheng, X., Zhang, Z., Zhong, C.-Q., Wan, H., Xiao, M., Lin, X., Feng, X.-H., & Han, J.
- Affiliations
- Xiamen University (CN)
- Baylor College of Medicine (US)
- Zhejiang University (CN)
- Corresponding author
- Han, Jiahuai
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-03-09
- Volume
- 17
- Issue
- 4
- Pages
- 434-444
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4523090
- OpenAlex
- W2049463960
- Cited by
- 161
- References
- 52
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 11 · 2023: 9 · 2022: 18 · 2021: 27 · 2020: 11 · 2019: 10 · 2018: 20 · 2017: 18 · 2016: 13 · 2015: 6
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA108454)
- National Institute of General Medical Sciences (R01GM063773)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR053591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- PPM1B, RIPK3, necroptosis, protein dephosphorylation, necrosome, MLKL, TNF-induced cell death, phosphatase, TNF-α, tissue damage
- MeSH terms
- Protein Phosphatase 2C, Animals, Cecum, Cell Line, HeLa Cells, Humans, Mice, Inbred C57BL, Phosphoprotein Phosphatases, Phosphorylation, Protein Kinases, Tumor Necrosis Factor-alpha, Signal Transduction, 3T3 Cells, Apoptosis, Mice, Knockout, RNA Interference, RNA, Small Interfering, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Gene Knockout Techniques
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