ArticleCell death & disease2022
Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Endoplasmic reticulum stress in skeletal muscle dysfunction of type 2 diabetes: mechanisms and therapeutic implications.Frontiers in endocrinology · 2026Review
- Identification and Validation of Glycosylation‑Related Genes in Ischemic Stroke Based on Bioinformatics and Machine Learning.Journal of molecular neuroscience : MN · 2025Article
- Hypermethylation ofAmerican journal of translational research · 2025Article
- Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression.Molecular cancer · 2024Review
- Let's make it personal: CRISPR tools in manipulating cell death pathways for cancer treatment.Cell biology and toxicology · 2024Review
- Regulation of RIPK1 Phosphorylation: Implications for Inflammation, Cell Death, and Therapeutic Interventions.Biomedicines · 2024Review
- The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis.BMC biology · 2024Article
- Oncogenic K-RasFEBS open bio · 2024Article
- The Function of Necroptosis and Its Treatment Target in IBD.Mediators of inflammation · 2024Review
- Protein phosphatase 6 promotes transforming growth factor-β signaling in mouse embryonic fibroblasts.The Journal of veterinary medical science · 2023Article
- Downregulation of BUBR1 regulates the proliferation and cell cycle of breast cancer cells and increases the sensitivity of cells to cisplatin.In vitro cellular & developmental biology. Animal · 2023Article
- Mechanisms of TNF-independent RIPK3-mediated cell death.The Biochemical journal · 2022Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Necroptotic cell death is mediated by a super-molecular complex called necrosome which consists of receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). The role of these kinases has been extensively investigated in the regulation of necroptosis. However, whether the protein phosphatase is involved in necroptosis is still largely unknown. Here, we identified protein phosphatase 6 catalytic subunit (PPP6C) promotes TNF-induced necroptosis by genome-wide CRISPR/Cas9 library screening. We found that PPP6C deficiency protects cells from TNF-induced necroptosis in a phosphatase-activity-dependent manner. Mechanistically, PPP6C acts as a TGF-β activated kinase 1 (TAK1) phosphatase to inactivate its kinase activity. Deletion of PPP6C leads to hyperactivation of TAK1 and reduced RIPK1 kinase activity upon TNF stimulation. We further showed that heterozygous deletion of Ppp6c in mouse gastrointestinal tract alleviates necroptosis-related tissue injury and inflammation. Thus, our study identifies PPP6C as an important regulator of necroptosis and highlights a central role of phosphatase in the regulation of necroptosis-related diseases.
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