| First Author | Geng J | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Issue | 1 | Pages | 359 |
| PubMed ID | 28842570 | Mgi Jnum | J:251915 |
| Mgi Id | MGI:5926457 | Doi | 10.1038/s41467-017-00406-w |
| Citation | Geng J, et al. (2017) Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat Commun 8(1):359 |
| abstractText | Stimulation of TNFR1 by TNFalpha can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFalpha leads to RIPK1-independent apoptosis when NF-kappaB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.TNFalpha can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision. |
