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

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2004 Jan 30

PMID 14749364

Citations 351

Authors

Kim Newton

Xiaoqing Sun

Vishva M Dixit

Affiliations

Soon will be listed here.

Abstract

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.

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References

Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T . Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999; 11(4):443-51. DOI: 10.1016/s1074-7613(00)80119-3. View

Pazdernik N, Donner D, Goebl M, Harrington M . Mouse receptor interacting protein 3 does not contain a caspase-recruiting or a death domain but induces apoptosis and activates NF-kappaB. Mol Cell Biol. 1999; 19(10):6500-8. PMC: 84620. DOI: 10.1128/MCB.19.10.6500. View

Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Liu Z . The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity. 2000; 12(4):419-29. DOI: 10.1016/s1074-7613(00)80194-6. View

Kasof G, Prosser J, Liu D, Lorenzi M, Gomes B . The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. FEBS Lett. 2000; 473(3):285-91. DOI: 10.1016/s0014-5793(00)01473-3. View

Lee E, Boone D, Chai S, Libby S, Chien M, Lodolce J . Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science. 2000; 289(5488):2350-4. PMC: 3582399. DOI: 10.1126/science.289.5488.2350. View

Sun X, Yin J, Starovasnik M, Fairbrother W, Dixit V . Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J Biol Chem. 2001; 277(11):9505-11. DOI: 10.1074/jbc.M109488200. View

Pohl T, Gugasyan R, Grumont R, Strasser A, Metcalf D, Tarlinton D . The combined absence of NF-kappa B1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc Natl Acad Sci U S A. 2002; 99(7):4514-9. PMC: 123679. DOI: 10.1073/pnas.072071599. View

Pomerantz J, Denny E, Baltimore D . CARD11 mediates factor-specific activation of NF-kappaB by the T cell receptor complex. EMBO J. 2002; 21(19):5184-94. PMC: 129028. DOI: 10.1093/emboj/cdf505. View

Zheng Y, Vig M, Lyons J, Van Parijs L, Beg A . Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med. 2003; 197(7):861-74. PMC: 2193891. DOI: 10.1084/jem.20021610. View

10.

Newton K, Dixit V . Mice lacking the CARD of CARMA1 exhibit defective B lymphocyte development and impaired proliferation of their B and T lymphocytes. Curr Biol. 2003; 13(14):1247-51. DOI: 10.1016/s0960-9822(03)00458-5. View

11.

Lewis M, Tartaglia L, Lee A, Bennett G, Rice G, Wong G . Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci U S A. 1991; 88(7):2830-4. PMC: 51333. DOI: 10.1073/pnas.88.7.2830. View

12.

Sun S, Ganchi P, Ballard D, Greene W . NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science. 1993; 259(5103):1912-5. DOI: 10.1126/science.8096091. View

13.

Stanger B, Leder P, Lee T, Kim E, Seed B . RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 1995; 81(4):513-23. DOI: 10.1016/0092-8674(95)90072-1. View

14.

Kontgen F, Grumont R, Strasser A, Metcalf D, Li R, Tarlinton D . Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 1995; 9(16):1965-77. DOI: 10.1101/gad.9.16.1965. View

15.

Snapper C, Zelazowski P, Rosas F, Kehry M, Tian M, Baltimore D . B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J Immunol. 1996; 156(1):183-91. View

16.

Doi T, Takahashi T, Taguchi O, Azuma T, Obata Y . NF-kappa B RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. J Exp Med. 1997; 185(5):953-61. PMC: 2196168. DOI: 10.1084/jem.185.5.953. View

17.

Kelliher M, Grimm S, Ishida Y, Kuo F, Stanger B, Leder P . The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity. 1998; 8(3):297-303. DOI: 10.1016/s1074-7613(00)80535-x. View

18.

Ghosh S, May M, Kopp E . NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998; 16:225-60. DOI: 10.1146/annurev.immunol.16.1.225. View

19.

Yu P, Huang B, Shen M, Quast J, Chan E, Xu X . Identification of RIP3, a RIP-like kinase that activates apoptosis and NFkappaB. Curr Biol. 1999; 9(10):539-42. DOI: 10.1016/s0960-9822(99)80239-5. View

20.

Sun X, Lee J, Navas T, Baldwin D, Stewart T, Dixit V . RIP3, a novel apoptosis-inducing kinase. J Biol Chem. 1999; 274(24):16871-5. DOI: 10.1074/jbc.274.24.16871. View