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Molecular and Cellular Biology, February 2004, p. 1464-1469, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1464-1469.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Kinase RIP3 Is Dispensable for Normal NF-Bs, Signaling by the B-Cell and T-Cell Receptors, Tumor Necrosis Factor Receptor 1, and Toll-Like Receptors 2 and 4

Kim Newton, Xiaoqing Sun, and Vishva M. Dixit^*

Molecular Oncology Department, Genentech, Inc., South San Francisco, California 94080

Received 29 August 2003/ Accepted 18 November 2003

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-B signaling, but whether RIP3 promotes or attenuates activation of the NF-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-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-1ß (IL-1ß), IL-6, and TNF production after LPS treatment. Thus, we can exclude RIP3 as an essential modulator of NF-B signaling downstream of several receptor systems.

Present address: Shanghai Genomics, Inc., Shanghai 201203, People's Republic of China.

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