Back to Search
Start Over
Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Apr 27; Vol. 287 (18), pp. 14863-72. Date of Electronic Publication: 2012 Feb 23. - Publication Year :
- 2012
-
Abstract
- Receptor-interacting protein kinase 1 (RIPK1) is an important component of the tumor necrosis factor receptor 1 (TNFR1) signaling pathway. Depending on the cell type and conditions, RIPK1 mediates MAPK and NF-κB activation as well as cell death. Using a mutant form of RIPK1 (RIPK1ΔID) lacking the intermediate domain (ID), we confirm the requirement of this domain for activation of these signaling events. Moreover, expression of RIPK1ΔID resulted in enhanced recruitment of caspase-8 to the TNFR1 complex II component Fas-associated death domain (FADD), which allowed a shift from TNF-induced necroptosis to apoptosis in L929 cells. Addition of the RIPK1 kinase inhibitor necrostatin-1 strongly reduced recruitment of RIPK1 and caspase-8 to FADD and subsequent apoptosis, indicating a role for RIPK1 kinase activity in apoptotic complex formation. Our study shows that RIPK1 has an anti-apoptotic function residing in its ID and demonstrates a cellular system as an elegant genetic model for RIPK1 kinase-dependent apoptosis that, in contrast to the Smac mimetic model, does not rely on depletion of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2).
- Subjects :
- Animals
Apoptosis Regulatory Proteins
Baculoviral IAP Repeat-Containing 3 Protein
Carrier Proteins genetics
Carrier Proteins metabolism
Caspase 8 genetics
Caspase 8 metabolism
Cell Line
Humans
Imidazoles pharmacology
Indoles pharmacology
Inhibitor of Apoptosis Proteins genetics
Inhibitor of Apoptosis Proteins metabolism
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Mice
Mitochondrial Proteins genetics
Mitochondrial Proteins metabolism
Mutation
Necrosis genetics
Necrosis metabolism
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Receptors, Tumor Necrosis Factor, Type I genetics
Receptors, Tumor Necrosis Factor, Type I metabolism
Tumor Necrosis Factor-alpha pharmacology
Ubiquitin-Protein Ligases
Apoptosis
MAP Kinase Signaling System
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22362767
- Full Text :
- https://doi.org/10.1074/jbc.M111.288670