Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1

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.