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Inactivation of host Rho GTPases is a widespread strategy employed by bacterial pathogens to manipulate mammalian cellular functions and avoid immune defenses. Some bacterial toxins mimic eukaryotic Rho GTPase-activating proteins (GAPs) to inactivate mammalian GTPases, probably as a result of evolutionary convergence. An intriguing question remains whether eukaryotic pathogens or parasites may use endogenous GAPs as immune-suppressive toxins to target the same key genes as bacterial pathogens. Interestingly, a RhoGAP domain-containing protein, LbGAP, was recently characterized from the parasitoid wasp Leptopilina boulardi, and shown to protect parasitoid eggs from the immune response of Drosophila host larvae. We demonstrate here that LbGAP has structural characteristics of eukaryotic RhoGAPs but that it acts similarly to bacterial RhoGAP toxins in mammals. First, we show by immunocytochemistry that LbGAP enters Drosophila immune cells, plasmatocytes and lamellocytes, and that morphological changes in lamellocytes are correlated with the quantity of LbGAP they contain. Demonstration that LbGAP displays a GAP activity and specifically interacts with the active, GTP-bound form of the two Drosophila Rho GTPases Rac1 and Rac2, both required for successful encapsulation of Leptopilina eggs, was then achieved using biochemical tests, yeast two-hybrid analysis, and GST pull-down assays. In addition, we show that the overall structure of LbGAP is similar to that of eukaryotic RhoGAP domains, and we identify distinct residues involved in its interaction with Rac GTPases. Altogether, these results show that eukaryotic parasites can use endogenous RhoGAPs as virulence factors and that despite their differences in sequence and structure, eukaryotic and bacterial RhoGAP toxins are similarly used to target the same immune pathways in insects and mammals. 相似文献
43.
Antosiewicz J Wielgus-Kutrowska B Długosz M Holy A Bzowska A 《Nucleosides, nucleotides & nucleic acids》2007,26(8-9):969-974
Complex formation of multisubstrate analogue inhibitor--2-amino-9-[2-(phosphonomethoxy)ethyl]-6-sulfanylpurine (PME-6-thio-Gua) with trimeric purine nucleoside phosphorylase from Cellulomonas sp. was investigated using a stopped-flow spectrofluorimetric approach. Results obtained indicate that, in contrast to binding of guanine, i.e., the transition-state conformation trapping ligand, for which binding at each active site is followed by the enzyme conformational change, association of the ground-state analogue PME-6-thio-Gua is a one-step process. 相似文献
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Bajgar J Hajek P Zdarova JK Kassa J Paseka A Slizova D Krs O Kuca K Jun D Fusek J Capek L 《Journal of enzyme inhibition and medicinal chemistry》2010,25(6):790-797
Tabun belongs to the most toxic nerve agents. Its mechanism of action is based on acetylcholinesterase (AChE) inhibition at the peripheral and central nervous systems. Therapeutic countermeasures comprise administration of atropine with cholinesterase reactivators able to reactivate the inhibited enzyme. Reactivation of AChE is determined mostly biochemically without specification of different brain structures. Histochemical determination allows a fine search for different structures but is performed mostly without quantitative evaluation. In rats intoxicated with tabun and treated with a combination of atropine and HI-6, obidoxime, or new oxime K048, AChE activities in different brain structures were determined using biochemical and quantitative histochemical methods. Inhibition of AChE following untreated tabun intoxication was different in the various brain structures, having the highest degree in the frontal cortex and reticular formation and lowest in the basal ganglia and substantia nigra. Treatment resulted in an increase of AChE activity detected by both methods. The highest increase was observed in the frontal cortex. This reactivation was increased in the order HI-6 < K048 < obidoxime; however, this order was not uniform for all brain parts studied. A correlation between AChE activity detected by histochemical and biochemical methods was demonstrated. The results suggest that for the mechanism of action of the nerve agent tabun, reactivation in various parts of the brain is not of the same physiological importance. AChE activity in the pontomedullar area and frontal cortex seems to be the most important for the therapeutic effect of the reactivators. HI-6 was not a good reactivator for the treatment of tabun intoxication. 相似文献
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Andreasen SØ Thomsen AR Koteliansky VE Novobrantseva TI Sprague AG de Fougerolles AR Christensen JP 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(6):2804-2811
Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, alpha(1)beta(1) and alpha(2)beta(1), on activated and memory T cells. Using this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of alpha(1)beta(1) and alpha(2)beta(1) can be rapidly induced on acutely activated T cells, that expression of alpha(1)beta(1) remains elevated on memory T cells, and that expression of alpha(1)beta(1) parallels that of viral-specific effector CD8(+) T cells (defined by tetramer and IFN-gamma staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar decreased responses were seen upon transfer of alpha(1)-deficient activated/memory T cells. Thus, expression of alpha(1)beta(1) and alpha(2)beta(1) integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect of alpha(1)beta(1) blockade on the delayed-type hypersensitivity response could be bypassed by direct injection of Ag-specific T cells to inflammatory sites, demonstrating for the first time in vivo that collagen-binding integrins are involved in leukocyte migration into tissues. 相似文献
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Antonin?BukovskyEmail author Maria?Cekanova Michael?R?Caudle Jay?Wimalasena James?S?Foster Donald?C?Henley Robert?F?Elder 《Reproductive biology and endocrinology : RB&E》2003,1(1):13
Estrogens play an important role in the regulation of placental function, and 17-beta-estradiol (E2) production rises eighty
fold during human pregnancy. Although term placenta has been found to specifically bind estrogens, cellular localization of
estrogen receptor alpha (ER-alpha) in trophoblast remains unclear. We used western blot analysis and immunohistochemistry
with h-151 and ID5 monoclonal antibodies to determine the expression and cellular localization of ER-alpha protein in human
placentae and cultured trophoblast cells. Western blot analysis revealed a ~65 kDa ER-alpha band in MCF-7 breast carcinoma
cells (positive control). A similar band was detected in five normal term placentae exhibiting strong expression of Thy-1
differentiation protein in the villous core. However, five other term placentae, which exhibited low or no Thy-1 expression
(abnormal placentae), exhibited virtually no ER-alpha expression. In normal placentae, nuclear ER-alpha expression was confined
to villous cytotrophoblast cells (CT), but syncytiotrophoblast (ST) and extravillous trophoblast cells were unstained. In
abnormal placentae no CT expressing ER-alpha were detected. Normal and abnormal placentae also showed ER-alpha expression
in villous vascular pericytes and amniotic (but not villous) fibroblasts; no staining was detected in amniotic epithelial
cells or decidual cells. All cultured trophoblast cells derived from the same normal and abnormal placentae showed distinct
ER-alpha expression in western blots, and the ER-alpha expression was confined to the differentiating CT, but not to the mature
ST. Trophoblast cells from six additional placentae were cultured in normal medium with phenol red (a weak estrogen) as above
(PhR+), or plated in phenol red-free medium (PhR-) without or with mid-pregnancy levels of E2 (20 nM). Culture in PhR- medium
without E2 caused retardation of syncytium formation and PhR-medium with E2 caused acceleration of syncytium formation compared
to cultures in PhR+ medium. These data indicate that the considerable increase in estrogen production during pregnancy may
play a role, via the ER-alpha, in the stimulation of CT differentiation and promote function in normal placentae. This mechanism,
however, may not operate in abnormal placentae, which show a lack of ER-alpha expression. 相似文献