| First Author | Jaco I | Year | 2017 |
| Journal | Mol Cell | Volume | 66 |
| Issue | 5 | Pages | 698-710.e5 |
| PubMed ID | 28506461 | Mgi Jnum | J:251943 |
| Mgi Id | MGI:6106690 | Doi | 10.1016/j.molcel.2017.05.003 |
| Citation | Jaco I, et al. (2017) MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Mol Cell 66(5):698-710.e5 |
| abstractText | TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-kappaB, p38alpha, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production. |
