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 cpdmrelated pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5476-5480 |
| Number of pages | 5 |
| Journal | Journal of Immunology |
| Volume | 192 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 2014 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
Cutting edge : RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. / Berger, Scott B.; Kasparcova, Viera; Hoffman, Sandy; Swift, Barb; Dare, Lauren; Schaeffer, Michelle; Capriotti, Carol; Cook, Michael; Finger, Joshua; Hughes-Earle, Angela; Harris, Philip A.; Kaiser, William; Mocarski, Edward S.; Bertin, John; Gough, Peter J.
In: Journal of Immunology, Vol. 192, No. 12, 15.06.2014, p. 5476-5480.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cutting edge
T2 - RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice
AU - Berger, Scott B.
AU - Kasparcova, Viera
AU - Hoffman, Sandy
AU - Swift, Barb
AU - Dare, Lauren
AU - Schaeffer, Michelle
AU - Capriotti, Carol
AU - Cook, Michael
AU - Finger, Joshua
AU - Hughes-Earle, Angela
AU - Harris, Philip A.
AU - Kaiser, William
AU - Mocarski, Edward S.
AU - Bertin, John
AU - Gough, Peter J.
PY - 2014/6/15
Y1 - 2014/6/15
N2 - 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 cpdmrelated pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.
AB - 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 cpdmrelated pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.
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U2 - 10.4049/jimmunol.1400499
DO - 10.4049/jimmunol.1400499
M3 - Article
VL - 192
SP - 5476
EP - 5480
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 12
ER -