Cutting Edge: RIP1 Kinase Activity Is Dispensable for Normal Development but Is a Key Regulator of Inflammation in SHARPIN-Deficient Mice
- 15 June 2014
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 192 (12), 5476-5480
- https://doi.org/10.4049/jimmunol.1400499
Abstract
RIP1 (RIPK1) kinase is a key regulator of TNF-induced NF-κB activation, apoptosis, and necroptosis through its kinase and scaffolding activities. Dissecting the balance of RIP1 kinase activity and scaffolding function in vivo during development and TNF-dependent inflammation has been hampered by the perinatal lethality of RIP1-deficient mice. In this study, we generated RIP1 kinase–dead (Ripk1K45A) mice and showed they are viable and healthy, indicating that the kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1K45A mice were specifically protected against necroptotic stimuli in vitro and in vivo, we crossed them with SHARPIN-deficient cpdm mice, which develop severe skin and multiorgan inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1K45A mice with the cpdm strain protected against all cpdm-related pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.Keywords
This publication has 17 references indexed in Scilit:
- Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiencyNature Immunology, 2012
- RIP1 is required for IAP inhibitor-mediated sensitization for TRAIL-induced apoptosis via a RIP1/FADD/caspase-8 cell death complexOncogene, 2012
- A novel role for RIP1 kinase in mediating TNFα productionCell Death & Disease, 2012
- RIP3 Finds Partners in CrimeCell, 2012
- RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response SyndromeImmunity, 2011
- The Emerging Role of Linear Ubiquitination in Cell SignalingScience Signaling, 2011
- FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammationNature, 2011
- Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-αCell, 2009
- RIP1, a kinase on the crossroads of a cell's decision to live or dieCell Death & Differentiation, 2007
- The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB SignalImmunity, 1998