Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (T(H)2) cells, but its role in T(H)2-related allergic diseases remains to be investigated. In this study we provide a strong correlation between SOCS-3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. SOCS-3 transgenic mice showed increased T(H)2 responses and multiple pathological features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant SOCS-3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased T(H)2 development. These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of T(H)2-mediated allergic immune disease, and suggest that SOCS-3 may be a new therapeutic target for the development of antiallergic drugs.
The Tn551 insertion site of the autolysisdeficient Staphylococcus aureus mutant RUSAL2 was cloned and used to identify the autolysis gene ati in the parent strain,RN450. The open reading frame for atl was 3768 bp in length, encoding a deduced protein of 1256 amino acids and molecular size of 137,381 Da. The atl gene product is a bifunctional protein that has an amidase domain and an endo-13-Nacetylglucosaminidase domain which must undergo proteolytic processing to generate the two extraceliular lytic enzymes found in the culture broth of S. aureus.
atl is a newly discovered autolysin gene in Staphylococcus aureus. The gene product, ATL, is a unique, bifunctional protein that has an amidase domain and a glucosaminidase domain. It undergoes proteolytic processing to generate two extracellular peptidoglycan hydrolases, a 51-kDa endo--N-acetylglucosaminidase and a 62-kDa N-acetylmuramyl-L-alanine amidase. It has been suggested that these enzymes are involved in the separation of daughter cells after cell division. We recently demonstrated that atl gene products are cell associated (unpublished data). The cell surface localization of the atl gene products was investigated by immunoelectron microscopy using anti-62-kDa N-acetylmuramyl-L-alanine amidase or anti-51-kDa endo--Nacetylglucosaminidase immunoglobulin G. Protein A-gold particles reacting with the antigen-antibody complex were found to form a ring structure on the cell surface at the septal region for the next cell division site. Electron microscopic examination of an ultrathin section of the preembedded sample revealed preferential distribution of the gold particles at the presumptive sites for cell separation where the new septa had not been completed. The distribution of the gold particles on the surface of protoplast cells and the association of the gold particles with fibrous materials extending from the cells suggested that some atl gene products were associated with a cellular component extending from the cell membrane, such as lipoteichoic acid. The formation of a ring structure of atl gene products may be required for efficient partitioning of daughter cells after cell division.Peptidoglycan hydrolases are a group of enzymes which catalyze the turnover or degradation of peptidoglycan in bacteria. They include N-acetylglucosaminidases, N-acetylmuramidases, N-acetylmuramyl-L-alanine amidases (AMs), endopeptidases, and transglycosylases (for reviews, see references 1, 18, 22, 25, 26, and 34). These enzymes degrade peptidoglycan saccules, resulting in cell lysis. Therefore, the activities of these enzymes should be strictly regulated. Various physiological functions of these enzymes have been proposed, including their roles in cell separation, wall growth, wall turnover, muropeptide recycling, sporulation, formation of flagella, and transformation (for reviews, see references 22, 25, 26, and 34). Peptidoglycan hydrolases have also been implicated in autolysis induced by -lactams or in bacterial pathogenesis (1, 2, 13-15, 19; for reviews, see references 22 and 26).Bacterial cell separation is a dynamic event in the cell cycle and requires cleavage of peptidoglycan connecting daughter cells. In many bacteria, correlation of a lack of peptidoglycan hydrolase(s) activity and a failure in cell separation has been reported (4,5,7,8,10,11,23,26,27,31,34,35). Recent studies have identified peptidoglycan hydrolases involved in cell separation in Listeria monocytogenes and in Lactococcus lactis (3, 36).We have previously described the identification of a 51-kDa endo--N-acetylglucosaminidase (GL) and a 62...
A Lyt-mutant with reduced autolytic activity was isolated after TnSSI mutagenesis of the methicillinsusceptible Staphylococcus aureus laboratory strain RN450. The Lyt-phenotype could be transferred back into the parent and into a variety of other S. aureus strains by transduction of the transposon marker. Southern analysis has located the Tn551 insert to a 3.2-kb HindIII DNA fragment on the SmaI B fragment of the staphylococcal chromosome. The Lyt-phenotype included reduced rates of cell wall turnover and autolysis induced by detergent or methicillin treatment; however, the rate of methicillin-induced killing was not affected. Peptidoglycans prepared from the parental and mutant cells showed identical muropeptide compositions, as resolved by a high-resolution high-pressure liquid chromatography technique. On the other hand, LiCl extracts of the mutant cells contained reduced amounts of total protein and lower specific cell wall-degrading activity compared with those of extracts of parental cells. The profile of bacteriolytic enzymes as detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed multiple band differences between mutant and parental cells; a major lytic band with properties characteristic of the staphylococcal endo-13-N-acetylglucosaminidase was completely absent from the Lyt-cells. The Lyt-phenotype transduced into a series of methicillin-resistant strains of both homogeneous and heterogeneous phenotypes caused only a modest decrease in the level of methicillin resistance, as determined by population analysis.Autolytic enzymes, i.e., enzymes that break covalent bonds in the bacterial cell wall, are widespread among bacteria (7, 16). The activities of at least some of these enzymes are clearly involved with phenomena such as bacterial autolysis (induced by antibiotics or adverse physiological conditions) and cell wall turnover. Although speculations concerning the involvement of autolysins in cell wall enlargement, cell division, and/or morphogenetic processes have been repeatedly considered, the physiological function(s) of autolysins for the bacterium remains to be elucidated (21). Recent improvements in the techniques for detection of autolysins indicate that bacteria may contain multiple and, in some cases, a surprisingly large number of autolytic enzymes (11,18), making the task of identification of physiological functions more complex.Staphylococcus aureus contains at least three kinds of catalytically distinct autolytic enzymes: an amidase, an N-acetyl endoglucosaminidase, and an endopeptidase (8,17,19,20). Molecular cloning of the glucosaminidase (1) and amidase (9) has been reported. Autolytic mutants of staphylococci have also been described (3, 10), and analyses of such mutants have yielded much interesting information about the control of these enzymes and their involvement with cell separation and wall turnover. Nevertheless, all of the mutants were generated by chemical mutagenesis, making a precise association of mutational site and phenotype difficult.In this commu...
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