| First Author | Lawlor KE | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 6282 | PubMed ID | 25693118 |
| Mgi Jnum | J:221796 | Mgi Id | MGI:5641574 |
| Doi | 10.1038/ncomms7282 | Citation | Lawlor KE, et al. (2015) RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun 6:6282 |
| abstractText | RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1beta inflammatory responses independent of MLKL and necroptotic cell death. |
