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    • LY 2389575 hydrochloride Plasminogen is composed of five N t

    2019-12-10

    Plasminogen is composed of five N-terminal kringle domains and a C-terminal serine protease domain. The kringle domains have an affinity to lysine and binding of plasminogen with its receptors is dependent on its lysine interacting kringle domains [10], [28]. In the current report, we show that enolase of Mtb is a surface localized, high affinity plasminogen binding receptor which binds to plasminogen in a lysine-mediated manner. Enolase bound plasminogen was also prone to urokinase mediated conversion into plasmin. Binding of plasminogen to the surface of Mtb and its conversion into fibrinolytic plasmin was reduced in the presence of anti-rEno antibodies. Also, immunization with recombinant enolase was found out to be protective upon infection with virulent Mtb strain (H37Rv) in mice, which was comparable to protection conferred by immunization with BCG and a known protective candidate Ag85B of Mtb[29], [30].
    Materials and Methods
    Results
    Discussion The ability of pathogens to modulate the host fibrinolytic system is a crucial characteristic for tissue invasion. Plasminogen is an abundant protein of the host fibrinolytic system which upon activation into plasmin dissolves fibrin clots [12]. Either using an endogenously expressed plasminogen activator or through sub-version of host plasminogen activators, pathogens have evolved a strategy to activate plasminogen and manipulate plasmin activity for their benefit. Recruitment of plasminogen to surface, even without activation, assists in bacterial adhesion [40]. Plasmin activity also leads to degradation of ECM proteins like collagen, fibronectin and laminin, facilitating dissemination and disease spread. Such is the significance of plasmin activity for some pathogens like Yersinia pestis and Salmonella enterica that they even cause degradation of host plasminogen activator inhibitors (PAIs) to facilitate tissue destruction [41]. Many of such plasminogen receptors in pathogens are surface localized metabolic LY 2389575 hydrochloride [10], [13], [14], [15], [16], with an unknown mechanism of export. There are many proteins across bacterial species which lack any kind of secretory signal peptide and are not characterized in relation to their export into the extracellular environment [42]. The moonlighting glycolytic enzymes are one of the most widely studied regulators in pathogens with respect to their interaction with host plasminogen. Despite of being one of the major bacterial diseases that have high human mortality, there are very few studies that focus on the moonlighting proteins of Mtb, the causative agent of TB. Plasminogen binding capacity of Mtb has been confirmed previously by some reports [43], [44]. Although there is no report of the interaction of Mtb enolase with plasminogen, there are a few reports which suggest the presence of enolase in the membrane and pellicle fractions of Mtb[45], [46]. An earlier study reported the identification of 15 Mtb proteins: DnaK, GroES, GlnA1, Ag85 complex, Mpt51, Mpt64, PrcB, MetK, SahH, Lpd, Icl, Fba and EF-Tu as putative plasminogen receptors present in the soluble and culture filtrate extracts of the bacilli [44]. Experimentally, three of them, DnaK, GlnA1 and Ag85B were shown to bind to plasminogen. Interestingly, Ag85B and DnaK, both have been shown to have protective roles against virulent Mtb challenge [30]. Another study reported the surface localization and binding of fructose-1,6-bisphosphate aldolase from Mtb to plasminogen [47]. We have shown here that enolase is present on the surface of Mtb and acts as a host plasminogen binding moonlighting glycolytic enzyme. Humans express three isoforms of enolase- alpha, beta and gamma. The alpha isoform predominates in most of the body tissues, the beta isoform is mainly present in the muscle and the gamma isoform is mostly localized to neuronal tissue [48]. The amino acid sequence identity between Mtb and human enolases is: 51% identity with alpha-enolase, 52% identity with beta-enolase and 54% identity with gamma-enolase (Supplementary Fig. S6).