The mitochondrial antiviral signaling protein (MAVS) mediates the activation of NFkappaB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFkappaB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs). However, MAVS was not required for interferon induction by cytosolic DNA or by Listeria monocytogenes. Mice lacking MAVS were viable and fertile, but they failed to induce interferons in response to poly(I:C) stimulation and were severely compromised in immune defense against viral infection. These results provide the in vivo evidence that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.

The protein kinase TAK1 mediates the activation of NF-B in response to stimulation by proinflammatory cytokines and microbial pathogens in the innate immunity pathways. However, the physiological function of TAK1 in the adaptive immunity pathways is unclear. By engineering mice lacking TAK1 in T cells, here, we show that TAK1 is essential for thymocyte development and activation in vivo. Deletion of TAK1 prevented the maturation of single-positive thymocytes displaying CD4 or CD8, leading to reduction of T cells in the peripheral tissues. Thymocytes lacking TAK1 failed to activate NF-B and JNK and were prone to apoptosis upon stimulation. Our results provide the genetic evidence that TAK1 is required for the activation of NF-B in thymocytes and suggest that TAK1 plays a central role in both innate and adaptive immunity.T he Rel͞NF-B family of transcription factors regulates the expression of a plethora of genes involved in inflammation, immunity, and apoptosis (1, 2). NF-B is normally sequestered in the cytoplasm of unstimulated cells through its association with the I B family of inhibitory proteins. Stimulation of cells with a variety of agents leads to the rapid phosphorylation and subsequent degradation of I B by the ubiquitin-proteasome pathway, thus allowing NF-B to enter the nucleus to turn on various target genes.Phosphorylation of I B is catalyzed by a large kinase complex consisting of I B kinase (IKK)␣, IKK␤, and NEMO (also known as IKK␥ or IKKAP). The IKK complex integrates signals from diverse pathways, including those emanating from the receptors for TNF␣ and IL-1␤, Toll-like receptors (TLRs), and T cell receptors (TCRs) (3-6). Stimulation of IL-1R and some TLRs leads to the recruitment of several proteins, including the adaptor MyD88, the kinases IRAK4 and IRAK1, and the ubiquitin ligase TRAF6. TRAF6 functions in conjunction with the ubiquitin-conjugating enzyme (E2) complex Ubc13-Uev1A to catalyze the synthesis of Lys-63-linked polyubiquitin chains on certain protein targets, including TRAF6 itself (7,8). Polyubiquitinated TRAF6 activates a protein kinase complex consisting of the TAK1 kinase and the adaptor proteins TAB1 and TAB2 (8, 9). The activation of TAK1 by TRAF6 requires the binding between the K63 polyubiquitin chains and a conserved novel zinc finger (NZF) domain of TAB2 or its homologue TAB3 (10). After TAK1 is activated, it phosphorylates IKK␤ within the activation loop, resulting in the activation of IKK. TAK1 also phosphorylates and activates MKK6 and MKK7, leading to the activation of p38 and JNK kinase pathways.Recent studies have shown that TRAF-mediated polyubiquitination and the TAK1 kinase complex also play an important role in NF-B activation in T cells (11). Stimulation of TCR by an antigenic peptide and its cognate MHC activates a tyrosine kinase phosphorylation cascade, which, in turn, leads to the activation of protein kinase (PK)C . PKC then triggers the recruitment of the CARD domain proteins CARMA1 and BCL10 and the paracaspase MALT1 to lipid rafts (12)(13)(14). MALT1 ...

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The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short halflife and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species.

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Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.

An enhancement near threshold is observed in the omega(phi) invariant mass spectrum from the doubly Okubo-Zweig-Iizuka-suppressed decays of J/psi-->gamma(omega)phi, based on a sample of 5.8 x 10(7) J/psi events collected with the BESII detector. A partial wave analysis shows that this enhancement favors JP=0+, and its mass and width are M=1812(+19)(-26)(stat)+/-18(syst) MeV/c2 and Gamma=105+/-20(stat)+/-28(syst) MeV/c2. The product branching fraction is determined to be B(J/psi-->gammaX)B(X-->omega(phi))=[2.61+/-0.27(stat)+/-0.65(syst)]x10(-4).