MASTering toxins Endothelin-1 (ET-1), a potent vasoconstrictor produced by mast cells, induces mast cells to release proteases that degrade ET-1 via the endothelin A receptor (ETA). In Nature, Galli and colleagues investigated the function of ET-1-mast cell interactions in vivo. Using mast cell-deficient mice, they showed ETA-dependent mast cell activation reduced morbidity associated with ET-1 administration. Chymase, produced by mast cells after ETA-dependent activation, reduced ET-1 concentrations in vivo. ETA-dependent mast cell protease release during acute bacterial peritonitis also reduced endogenous ET-1 concentrations and prolonged survival. These data suggest an additional function for mast cells is to promote homeostasis by limiting the toxicity of ET-1. It is presently unclear whether mast cells also regulate the toxicity of other naturally occurring compounds. JDKW
Outsourcing growth Activated Ras protooncogene, which is common in about a quarter of all human neoplasms, drives tumorigenic properties such as endothelial cell−mediated angiogenesis. To understand how Ras promotes the interaction between a tumor and its environment, Sparmann and Bar-Sagi examined genes induced by activated Ras. Reporting in Cancer Cell, they identify interleukin-8 (IL-8) as a major Ras-induced protein. IL-8 recruits endothelial cells during early tumor development. Concomitantly, inflammatory cells such as macrophages and granulocytes, which are critical in angiogenesis, infiltrate the core of the tumor before neovascularization. Thus, in addition to augmenting cell survival and cycling, activated Ras supports cancer progression in a cell nonautonomous manner. PTL
Cancer Cell6, 447−458 (2004)
New tricks for old dogs The complement system is an ancient form of innate immunity elicited upon infection. Although several pathways initiate complement activation, these converge at the C3 proteolytic cleavage step. Release of C3a, an anaphylatoxin, serves to recruit immune cells to the site of inflammation. In the Proceedings of the National Academy of Science, Nordahl et al. show that C3a and C3a-desArg (the peptide resulting after carboxypeptidase N action and which lacks anaphylatoxin activity), but not the holoprotein C3, have direct antimicrobial activity. These peptide fragments adopt helical conformations and can insert into and disrupt bacterial plasma membranes. Pure peptides could lyse multiple bacterial species when plated onto agar. Thus, C3a has additional roles beyond its ability to call in the troops. LAD
Proc. Natl. Acad. Sci. USA101, 16879−16884 (2004)
Vif destruction box HIV encodes viral infectivity factor (Vif), which allows it to overcome the antiviral mutating activity of host cellular APOBEC3G. Earlier work revealed that Vif targets APOBEC3G for proteasome-mediated destruction. Two reports in Genes & Development look at the molecular mechanism by which Vif exerts this effect. Mehle et al. and Yu et al. show Vif contains a SOCS-box that mediates protein interaction with the cullin E3 ubiquitin ligase complex composed of Cul5, ElonginB (EloB) and EloC. Vif mutations in or around the SOCS box prevent binding to Cul5 or EloC, but Vif still binds APOBEC3G. These mutants have reduced infectivity, as APOBEC3G is not destroyed. Mehle et al. also show that Vif phosphorylation blocks EloC interaction, hinting at another role for modified Vif. LAD
Genes Dev.18, 2861−2866 & 2867−2872 (2004)
Chewing closer to the fat CD1d-restricted NKT cells are thought to be important in controlling autoimmunity, malignancy and infection. However, the definitive endogenous ligand presented by CD1d has been enigmatic, hampering a better understanding of the development and function of these cells. In Science, Zhou et al. find that mice deficient in the lysosomal glycosphingolipid-degrading enzyme Hexb have a defect in NKT cell development. This observation leads to the identification of isoglobotrihexosylceramide (iGb3), which is critical for the natural 'autoreactivity' of both mouse and human NKT cells toward CD1d. Hence, iGb3 seems to be an important endogenous ligand that mediates NKT cell activation and development. Final confirmation of the role of iGb3 awaits its purification and characterization in mouse and humans. PTL
Science doi 10.1126/science.113440 (11 November 2004)
Possible HIV vaccine candidate Many pathogens use lipid rafts and caveolae, a specialized lipid raft containing the scaffolding protein caveolin-1, to mediate cell entry. In Immunity, Krust and colleagues show that the HIV-1 envelope glycoprotein gp41 contains a highly conserved caveolin-1 binding motif. Caveolin-1 bound synthetic peptides (called CBD1) containing the gp41 caveolin-1 binding motif. Indeed, gp41 from HIV-infected cells immunoprecipitated with caveolin-1. Immunization of rabbits with CBD1 peptide elicited antibodies that could inhibit infection of primary CD4+ T lymphocytes not only by certain laboratory-adapted and drug-resistant HIV-1 isolates, but also by HIV-1 isolates from clades A−G. This broad activity of CBD1 antibodies suggests that the gp41 caveolin binding motif could be a promising candidate for a B cell epitope vaccine. JDKW
Immunity21, 617−627 (2004)
Fly ointment Recognition of fungi or bacteria by Drosophila invokes the production of antimicrobial peptides. Drosophila express three proteoglycan recognition proteins (PGRP) that provide the substrate specificity required to mount immune responses appropriate for the invading pathogen. PGRP-SA activates the Toll pathway whereas PGRP-LC activates imd in response to bacteria containing diaminopimelic acid or lysine cross-linked structures, respectively. In The EMBO Journal, Kurata and colleagues show that PGRP-LE is cleaved and released into the hemolymph and is redundant with PRGP-LC in inducing imd. Whereas PGRP-LC appears to act in a cell-autonomous manner, PRGP-LE acts on multiple cells and is required to activate prophenoloxidase (proPO), necessary for wound healing and melanization after infection. Thus, PRGP-LE plays multiple roles necessary for Drosophila immunity. LAD
EMBO J.23, 4690−4700 (2004)
Written by Laurie A. Dempsey, Peter T. Lee and Jamie D.K. Wilson.
