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A virally encoded shield against cellular immune function
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!¸ii!i!!!+!i!i!!iiiii i!i! i ¸ii!iliii!!ii! ¸+il ¸¸i!i A virally encoded shield against cellular immune function UPTON, C., MOSSMAN, K. and MCFADDEN, G. (1992) Encoding of a homolog of the IFN-7receptor by myxoma virus Science258, 1369-1372 The mechanisms by which the cellular immune system combats the spread of viral infection have become especially critical in this era of AIDS. Cellular immune responses to a variety of viral infections are aimed at the destruction of the infected cells and the generation of an antiviral state in the surrounding cells. These effects are induced by cytokines binding to their cognate receptors; for example, interferon-7 (IFN-7) is produced by activated T cells and NK cells, and is an important activator of macrophages. Myxoma virus, which is studied as a model for poxvirus virulence, can overwhelm the host immune response in part due to a 'decoy strategy'. Upton et al. show that the major secreted protein from myxoma-virus-infected cells (the T7 gene product) is homologous to human and mouse IFN-7 receptors. In vitro, the T7 protein binds IFN-7 specifically, and IFN-7 fails to induce an antiviral state in cells that have been treated with TT-containing supernatants from myxoma-virus-infected cells. Thus myxoma virus short-circuits the cellular immune response by preventing IFN-7 from binding to and activating its cognate cellular receptor. This research group has also demonstrated the production of a homologue of the tumour necrosis factor receptor by myxoma virus as an anti-antiviral factor. Eukaryotic viruses have been instrumental as models for cellular DNA replication and gene expression. Studying the targeting by poxviruses of critical elements of the host antiviral system may uncover some crucial but as yet unidentified aspects of the cellular immune response.
Linking tyroslne kinases to Ras ROZAKIS-ADCOCK, M. et oL (1992) Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases Nature 360, 689-692 This paper describes another link in the 'chain' of protein-protein interactions that couple signalling by tyrosine kinases to the Ras guanine-nucleotidebinding protein. The mammalian Shc proteins have been implicated in a mitogenic signalling pathway from tyrosine kinases: they transform cells when overexpressed, they are phosphorylated by tyrosine kinases, and they bind activated growth factor receptors through a C-terminal SH2 domain. Rozakis.Adcock et aL now report the association of phosphorylated Shc with Grb2 (the mammalian homologue of Caenorhabditis elegans Sem5), an SH2and SH3-containing protein thought to activate Ras in response to tyrosine kinase signalling but that is not itself a tyrosine kinase substrate. The authors show by coimmunoprecipitation that tyrosine-phosphorylated Shc in v-src-transformed cells associates with Grb2. This association is also seen after EGF stimulation of rat fibroblasts overexpressing the EGF receptor. In this case the complex contains the autophosphorylated EGF receptor as well. Shc association with certain Grb2 fusion products in vitro was used to show that interaction occurs through the Grb2 SH2 domain. Functional evidence suggesting Shc proteins are indeed involved in the control of Ras signalling through Grb2 was provided by studies of Ras-dependent neurite extension in PC12 cells in response to I,~GF. NGF stimulation of these cells induces tyrosine phosphorylation of Shc proteins and formation of the Shc-Grb2 complex. Furthermore, overexpression of shc induced neurite extension and this effect could be blocked by a dominant inhibitory Ras. 80
CentHole-associated proteins in
Chlamydomonas TAILLON, B. E., ADLER, S. A., SUHAN, J. P. and JARVlK, J. W. (1992) Mutational analysis of centrin: an EF-hand protein associated with three distinct contractile fibers in the basal body apparatus of Chlamydomonas J. Cell BioL 119, 1613-1624 The biflagellate green alga Chlamydomonas has been an important organism for genetic and biochemical studies of centrioles and their associated proteins. Here Taillon et al. have determined the specific defect in a mutant, vfl2, that has a variable number of flagella. It turns out that the defect is a single base change in codon 101 (Glu to Lys) of the gene that encodes centrin, a ubiquitous Ca2*-binding contractile protein. In Chlamydomonas, centrin is present in three structures, all of which are centriole-associated: the contractile fibres that join the centriole pair to the nucleus, the transition region between the centriole and the axoneme, and the striated fibre that connects the two centrioles. The specific alteration in the vfl2 mutant occurs within the third Ca2+binding domain of centrin and affects the localization and function of centrin in all three locations. Interestingly, certain phenotypic revertant strains retain ultrastructural defects in the distal striated fibre. When the sequence of centrin in these pseudorevertants was examined, new alterations were found at codon 101. Thus, Lys at codon 101 produces global defects in centrin function, as seen in the original vfl2 strain, whereas Met or lie at this position affects only striated fibre formation. Analyses such as this should continue to provide general insights into the function of Ca2+-binding proteins, as well as specific insights into centriole function.
HEADLINES HEADLINESare contributedregularly by a panelof researchscientists appointed by the Editor. Scientists interested in joining the panelshould contact TCB.
TRENDS IN CELLBIOLOGYVOL. 3 MARCH 1993
!¸ii!i!!!+!i!i!!iiiii i!i! i ¸ii!iliii!!ii! ¸+il ¸¸i!i A virally encoded shield against cellular immune function UPTON, C., MOSSMAN, K. and MCFADDEN, G. (1992) Encoding of a homolog of the IFN-7receptor by myxoma virus Science258, 1369-1372 The mechanisms by which the cellular immune system combats the spread of viral infection have become especially critical in this era of AIDS. Cellular immune responses to a variety of viral infections are aimed at the destruction of the infected cells and the generation of an antiviral state in the surrounding cells. These effects are induced by cytokines binding to their cognate receptors; for example, interferon-7 (IFN-7) is produced by activated T cells and NK cells, and is an important activator of macrophages. Myxoma virus, which is studied as a model for poxvirus virulence, can overwhelm the host immune response in part due to a 'decoy strategy'. Upton et al. show that the major secreted protein from myxoma-virus-infected cells (the T7 gene product) is homologous to human and mouse IFN-7 receptors. In vitro, the T7 protein binds IFN-7 specifically, and IFN-7 fails to induce an antiviral state in cells that have been treated with TT-containing supernatants from myxoma-virus-infected cells. Thus myxoma virus short-circuits the cellular immune response by preventing IFN-7 from binding to and activating its cognate cellular receptor. This research group has also demonstrated the production of a homologue of the tumour necrosis factor receptor by myxoma virus as an anti-antiviral factor. Eukaryotic viruses have been instrumental as models for cellular DNA replication and gene expression. Studying the targeting by poxviruses of critical elements of the host antiviral system may uncover some crucial but as yet unidentified aspects of the cellular immune response.
Linking tyroslne kinases to Ras ROZAKIS-ADCOCK, M. et oL (1992) Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases Nature 360, 689-692 This paper describes another link in the 'chain' of protein-protein interactions that couple signalling by tyrosine kinases to the Ras guanine-nucleotidebinding protein. The mammalian Shc proteins have been implicated in a mitogenic signalling pathway from tyrosine kinases: they transform cells when overexpressed, they are phosphorylated by tyrosine kinases, and they bind activated growth factor receptors through a C-terminal SH2 domain. Rozakis.Adcock et aL now report the association of phosphorylated Shc with Grb2 (the mammalian homologue of Caenorhabditis elegans Sem5), an SH2and SH3-containing protein thought to activate Ras in response to tyrosine kinase signalling but that is not itself a tyrosine kinase substrate. The authors show by coimmunoprecipitation that tyrosine-phosphorylated Shc in v-src-transformed cells associates with Grb2. This association is also seen after EGF stimulation of rat fibroblasts overexpressing the EGF receptor. In this case the complex contains the autophosphorylated EGF receptor as well. Shc association with certain Grb2 fusion products in vitro was used to show that interaction occurs through the Grb2 SH2 domain. Functional evidence suggesting Shc proteins are indeed involved in the control of Ras signalling through Grb2 was provided by studies of Ras-dependent neurite extension in PC12 cells in response to I,~GF. NGF stimulation of these cells induces tyrosine phosphorylation of Shc proteins and formation of the Shc-Grb2 complex. Furthermore, overexpression of shc induced neurite extension and this effect could be blocked by a dominant inhibitory Ras. 80
CentHole-associated proteins in
Chlamydomonas TAILLON, B. E., ADLER, S. A., SUHAN, J. P. and JARVlK, J. W. (1992) Mutational analysis of centrin: an EF-hand protein associated with three distinct contractile fibers in the basal body apparatus of Chlamydomonas J. Cell BioL 119, 1613-1624 The biflagellate green alga Chlamydomonas has been an important organism for genetic and biochemical studies of centrioles and their associated proteins. Here Taillon et al. have determined the specific defect in a mutant, vfl2, that has a variable number of flagella. It turns out that the defect is a single base change in codon 101 (Glu to Lys) of the gene that encodes centrin, a ubiquitous Ca2*-binding contractile protein. In Chlamydomonas, centrin is present in three structures, all of which are centriole-associated: the contractile fibres that join the centriole pair to the nucleus, the transition region between the centriole and the axoneme, and the striated fibre that connects the two centrioles. The specific alteration in the vfl2 mutant occurs within the third Ca2+binding domain of centrin and affects the localization and function of centrin in all three locations. Interestingly, certain phenotypic revertant strains retain ultrastructural defects in the distal striated fibre. When the sequence of centrin in these pseudorevertants was examined, new alterations were found at codon 101. Thus, Lys at codon 101 produces global defects in centrin function, as seen in the original vfl2 strain, whereas Met or lie at this position affects only striated fibre formation. Analyses such as this should continue to provide general insights into the function of Ca2+-binding proteins, as well as specific insights into centriole function.
HEADLINES HEADLINESare contributedregularly by a panelof researchscientists appointed by the Editor. Scientists interested in joining the panelshould contact TCB.
TRENDS IN CELLBIOLOGYVOL. 3 MARCH 1993