Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4.
RIP3 is a member of the RIP kinase family. It is expressed in the embryo and in multiple adult tissues, including most hemopoietic cell lineages. Several studies have implicated RIP3 in the regulation of apoptosis and NF-kappa B signaling, but whether RIP3 promotes or attenuates activation of the NF-kappa B family of transcription factors has been controversial. We have generated RIP3-deficient mice by gene targeting and find RIP3 to be dispensable for normal mouse development. RIP3-deficient cells showed normal sensitivity to a variety of apoptotic stimuli and were indistinguishable from wild-type cells in their ability to activate NF-kappa B signaling in response to the following: human tumor necrosis factor (TNF), which selectively engages mouse TNF receptor 1; cross-linking of the B- or T-cell antigen receptors; peptidoglycan, which activates Toll-like receptor 2; and lipopolysaccharide (LPS), which stimulates Toll-like receptor 4. Consistent with these observations, RIP3-deficient mice exhibited normal antibody production after immunization with a T-dependent antigen and normal interleukin-1 beta (IL-1 beta), IL-6, and TNF production after LPS treatment. Thus, we can exclude RIP3 as an essential modulator of NF-kappa B signaling downstream of several receptor systems.
Newton
Kim
K
Molecular Oncology Department, Genentech, Inc., South San Francisco, California 94080, USA.
Sun
Xiaoqing
X
Dixit
Vishva M
VM
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D017353:Gene Deletion; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
D015703:Antigens, CD; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse