A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response

Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2-3 million lives from tuberculosis worldwide. Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis, there is mounting evidence that considerable heterogeneity exists in molecules important in disease pathogenesis. These differences may manifest in the ability of some isolates to modify the host cellular immune response, thereby contributing to the observed diversity of clinical outcomes. Here we describe the identification and functional relevance of a highly biologically active lipid species-a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of M. tuberculosis isolates belonging to the W-Beijing family that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by M. tuberculosis or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner.     

A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism

Pathogenic bacteria often use effector molecules to increase virulence. In most cases, the mode of action of effectors remains unknown. Strains of Pseudomonas syringae pv. syringae (Pss) secrete syringolin A (SylA), a product of a mixed non-ribosomal peptide/polyketide synthetase, in planta. Here we identify SylA as a virulence factor because a SylA-negative mutant in Pss strain B728a obtained by gene disruption was markedly less virulent on its host, Phaseolus vulgaris (bean). We show that SylA irreversibly inhibits all three catalytic activities of eukaryotic proteasomes, thus adding proteasome inhibition to the repertoire of modes of action of virulence factors. The crystal structure of the yeast proteasome in complex with SylA revealed a novel mechanism of covalent binding to the catalytic subunits. Thus, SylA defines a new class of proteasome inhibitors that includes glidobactin A (GlbA), a structurally related compound from an unknown species of the order Burkholderiales, for which we demonstrate a similar proteasome inhibition mechanism. As proteasome inhibitors are a promising class of anti-tumour agents, the discovery of a novel family of inhibitory natural products, which we refer to as syrbactins, may also have implications for the development of anti-cancer drugs. Homologues of SylA and GlbA synthetase genes are found in some other pathogenic bacteria, including the human pathogen Burkholderia pseudomallei, the causative agent of melioidosis. It is thus possible that these bacteria are capable of producing proteasome inhibitors of the syrbactin class.     

RBM5蛋白调控c-FLIP差异性剪切及其抑制A549增殖的研究

本文试探讨RBM5蛋白对肺腺癌细胞A549增殖的影响及其作用机制,以期为开辟肺癌基因治疗新途径提供帮助.本研究构建了表达RBM5基因的真核表达载体,并转染A549细胞株,增强其中该基因的表达量.采用RT-PCR检测转染后A549细胞中c-FLIP基因不同剪切体的表达量,并绘制生长曲线.结果表明,RBM5基因在A549细胞中的高表达,可以调控c-FLIP的差异剪切,减少c-FLIP-S的表达量,激活细胞程序化死亡相关通路,抑制肺腺癌细胞恶性增殖.     

A new mechanism of invader success： Exotic plant inhibits natural vegetation restoration by changing soil microbe community

Since the 1950s of the last century, the exotic plant, Eupatorium adenophorum, has spread rapidly across southwest China, damaging native ecosystems and causing great economic losses. We examined the pH, N, P, K, and organic matter concentrations, and the bacterial community character (by Biolog EcoPlateTM) in soils from sites heavily and lightly invaded by this exotic species. Also, soil from the lightly invaded site was treated with a water extract of E.adenophorum roots to examine the effect of the plant on soil properties. We grew three plant species, one native and two exotic, in pot experiment using soil from heavily invaded site to examine the effects of the soil on these plants growth. The soil analysis demonstrated that the pH, organic matter, total N, total P and total K in soils from the heavily invaded site were only slightly different from those of the lightly invaded site, but concentrations of NH4^ , NO3^- and available P and K in the heavily invaded site were greater than those in the lightly invaded site. The catabolic activity of soil bacterial community in the heavily invaded site was different from that in the lightly invaded site. The catabolic activity of bacterial community in soils treated by the water extract of E.adenophorum roots changed and became similar to that in soils from the heavily invaded site. The pot experiment showed that the exotic plants growth in heavily invaded soil were not different from in lightly invaded soil; however, the native plant biomass decreased dramatically when grown in soil from the heavily invaded site as compared to soil from the lightly invaded site; and the same phenomenon was found when any potential allelopathic effects by E. adenophorum were eliminated by added activated carbon to those soils. Difference in soil nutrient availability and allelopathy could not explain this phenomenon of the native plant in the soils from the heavily and lightly invaded sites. Changes observed in the soil bacterial community were obviously related to native plant growth in those tow soils. Those results suggest that changing soil microbial community may be an important part of E. adenophorum invasion process. Since the soil microbial community serves as bridge in connection of exotic and natural plants, the exotic plant could inhibit the natural plant growth and reproduction by changing the soil microbial community in invaded site.