New NF-κB subunit

Native NF-κB complexes bind with greater affinity to the immunoglobulin (Ig) κB DNA sequence than NF-κB complexes that are generated from purified p65 and p50 proteins, suggesting that native NF-κB complexes might contain factors that enhance interaction with DNA consensus sites. In Cell, Wan et al. implicate the ribosomal protein RPS3 as one such factor. Identified during a screen for p65-binding proteins, ribosomal protein S3 (RPS3) bound to, but translocated to the nucleus independently of, p65 in Jurkat cells subjected to T cell receptor or tumor necrosis factor stimulation. RPS3 is required for maximal p65 binding to and transcription of some (interleukin 2, IκBα, Igκ), but not other (CD25, CD69), physiologically important NF-κB–inducible genes. Future work is needed to identify the intracellular signals regulating RPS3 subcellular localization and to understand why RPS3 binds to and enhances expression of only a subset of NF-κB–dependent genes. CB

Cell 131, 927–939 (2007)

Virus assault on apoptosis

On virus infection, cells may initiate apoptosis to limit virus dissemination. In PLOS Pathogens, Feng et al. report that murine γ-herpesvirus 68 (MHV-68) open reading-frame M8 encodes a protein termed viral mitochondrial anti-apoptotic protein (vMAP) that is necessary and sufficient for preventing mitochondrial-dependent apoptosis of infected cells. The N-terminal region of vMAP recruits anti-apoptotic protein Bcl-2 to mitochondria, which antagonizes apoptosis by facilitating Bcl-2 interaction with pro-apoptotic BH3-only proteins such as Bax and Bak. In addition, the C-terminal region of vMAP interacts with the voltage-dependent anion channel (VDAC) to prevent mitochondrial release of pro-apoptotic cytochrome c. Although deletion of either region of vMAP significantly impaired its anti-apoptotic function, N-terminal–mediated vMAP regulation of Bcl-2 has a greater anti-apoptotic effect. Mutant MHV-68 lacking a functional vMAP gene replicated 10–30-fold less well in wild-type mouse embryonic fibroblasts (MEFs); this defect could be complemented by deletion of both Bax and Bak in MEFs. These data demonstrate a previously unknown, dual anti-apoptotic function of a virus-encoded protein. DCB

PLOS Pathog. 3, 1849–1865 (2007)

Role for cyclic prostaglandins

Cyclic prostaglandins arise by metabolism of arachidonic acid, but whether these labile compounds have an in vivo role is controversial. In the Proceedings of the National Academy of Science, Rajakariar et al. show that formation of 15deoxyΔ12–14-PGJ2 (15d-PGJ2), a cyclic derivative of PGD2 that is generated downstream of cyclooxygenase activity, regulates leukocyte trafficking at sites of inflammation. 15d-PGJ2 appears early in exudates and is required for leukocyte efflux to the draining lymph nodes. Mice lacking the synthase hPGD2S, which produces 15d-PGJ2, accumulated higher numbers of leukocytes during acute inflammation as compared with normal littermates, although administration of 15d-PGJ2 alleviated this effect. Mutant mice fail to resolve lesions as a result of an imbalance of inflammatory cytokines and chemokines. How 15d-PGJ2 mediates its protective effects via chemotactic signaling remains to be elucidated. LAD

Proc. Natl. Acad. Sci. USA 104, 20979–20984 (2007)

Lack of ROS, hyper-inflammation

Chronic granulomatous disease (CGD) is caused by recurring bacterial and fungal infections that are the result of defective reactive oxygen species (ROS) production by phagocytes that are deficient in NADPH oxidase activity. In Nature, Puccetti et al. found that a defect in tryptophan catabolism leads to unrestrained γδ T cell (Vγ1+) activity, including production of interleukin 17 (IL-17), in CGD. Using mice deficient for p47phox, an essential component of the phagocyte NADPH oxidase complex, and infection with A. fumigatus to induce experimental CGD, the authors found that production of IL-17 is required for destructive lung inflammation. Production of L-kynurenin, a product of normal tryptophan catabolism mediated by NADPH-produced ROS and inflammation-induced indoleamine 2,3-dioxygease (IDO), was defective in the p47phox knockout mice and in wild-type mice treated with an IDO inhibitor. Supplying exogenous L-kynurenin and interferon-γ restored production of metabolites downstream of the tryptophan defect. These data demonstrate that reduced ROS production paradoxically increases inflammatory T cell reactivity mediated by IL-17. DCB

Nature 451, 211–215 (2008)

miR-155 targets Pu.1

Mice lacking microRNA miRNA-155 show defective adaptive immune responses, including reduced germinal center formation. In Immunity, Vigorito et al. show that the defect is B cell intrinsic. B cells lacking miR-155 switched less efficiently to non-IgM isotypes, although synthesis and secretion of IgM in response to T-dependent and T-independent antigens was unimpaired and could not be rescued by Bcl-2. Likewise, expression of Aicda and the frequency of somatic mutations were not altered by a lack of miR-155. A search for mRNA targets of miR-155 identified Sfpi1, which encodes the transcription factor Pu.1. Sfpil contains a cognate recognition site for miR-155 in its 3′ UTR, which was verified using reporter constructs. After immunization, miR-155–deficient B cells failed to downregulate Pu.1 and B cells transduced with Pu.1 made less IgG1. Thus, miR-155 downregulates Pu.1 to allow switching to other isotypes. LAD

Immunity 27, 847–859 (2007)

Looping back

Phosphorylated by protein kinase C–β (PKCβ) in B cells, the adaptor CARMA1, by nucleating a complex with the adaptors Bcl-10 and MALT1, transmits BCR signals to the transcription factor NF-κB. In the Journal of Experimental Medicine, Kurosaki and colleagues show that IκB kinase–β (IKKβ), a downstream effector of the CARMA1–Bcl-10–MALT1 complex, actually 'loops back' to propagate BCR-driven phosphorylation of CARMA1. PKCβ is required for phosphorylation of only one of three serine and threonine residues whose mutation blocks BCR-induced activation of NF-κB. Although required for CARMA1 phosphorylation in T cells, the kinase PDK1 is dispensable for BCR-triggered CARMA1 phosphorylation. IKKβ, however, is essential for BCR-induced phosphorylation of a specific CARMA1 serine residue and for optimal formation of the CARMA1–Bcl-10–MALT1 complex. Future work is needed to search for additional kinases potentially involved in linking BCR stimulation with CARMA–Bcl-10–MALT1 complex formation. CB

J. Exp. Med. (17 December 2007) doi: 10.1084/jem.20070379

Written by Christine Borowski, Douglas C. Braaten & Laurie A. Dempsey