Binding and Activation of Human Plasminogen by
            <i>Mycobacterium tuberculosis</i>

Monroy, Verónica; Amador, Angelica; Ruiz, Blanca; Espinoza-Cueto, Patricia; Xolalpa, Wendy; Mancilla, Raúl; Espitia, Clara

doi:10.1128/iai.68.7.4327-4330.2000

Cited by 24 publications

(16 citation statements)

References 29 publications

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“…Similar results have also been published for Pg binding and activation to Mycobacterium tuberculosis (16). In the case of GAS, human (h)Pg interacts with high affinity, through its lysine binding sites (LBS), to the Pg-binding group-A M-like protein (PAM) of GAS and is activated to Pm by streptokinase (SK), which is produced by this GAS strain.…”

supporting

confidence: 75%

The Lack of Binding of VEK-30, an Internal Peptide from the Group A Streptococcal M-like Protein, PAM, to Murine Plasminogen Is due to Two Amino Acid Replacements in the Plasminogen Kringle-2 Domain

Figuera-Losada

Ploplis

et al. 2008

Journal of Biological Chemistry

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VEK-30, a 30-amino acid internal peptide present within a streptococcal M-like plasminogen (Pg)-binding protein (PAM)from Gram-positive group-A streptococci (GAS), represents an epitope within PAM that shows high affinity for the lysine binding site (LBS) of the kringle-2 (K2) domain of human (h)Pg. VEK-30 does not interact with this same region of mouse (m)Pg, despite the high conservation of the mK2-and hK2-LBS. To identify the molecular basis for the species specificity of this interaction, hPg and mPg variants were generated, including an hPg chimera with the mK2 sequence and an mPg chimera containing the hK2 sequence. The binding of synthetic VEK-30 to these variants was studied by surface plasmon resonance. The data revealed that, in otherwise intact Pg, the species specificity of VEK-30 binding in these two cases is entirely dictated by two K2 residues that are different between hPg and mPg, namely, Arg-220 of hPg, which is a Gly in mPg, and Leu-222 of hPg, which is a Pro in mPg, neither of which are members of the canonical K2-LBS. Neither the activation of hPg, nor the enzymatic activity of its activated product, plasmin (hPm), are compromised by replacing these two amino acids by their murine counterparts. It is also demonstrated that hPg is more susceptible to activation to hPm after complexation with VEK-30 and that this property is greatly reduced as a result of the R220G and L222P replacements in hPg. These mechanisms for accumulation of protease activity on GAS likely contribute to the virulence of PAM ؉

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supporting

confidence: 75%

The Lack of Binding of VEK-30, an Internal Peptide from the Group A Streptococcal M-like Protein, PAM, to Murine Plasminogen Is due to Two Amino Acid Replacements in the Plasminogen Kringle-2 Domain

Figuera-Losada

Ploplis

et al. 2008

Journal of Biological Chemistry

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“…However, the proteolytic activity of plasmin has been implicated in a number of pathological processes (2), including the invasion of tissues by bacteria (5,18,19). Although WSN virus provides the first example of a viral protein whose plasminogen-binding activity is required for the acquisition of virulence, we suggest that other viruses also take advantage of plasmin-induced proteolysis for enhanced virulence.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen-Binding Activity of Neuraminidase Determines the Pathogenicity of Influenza A Virus

Goto

Wells

Takada

et al. 2001

J Virol

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When expressed in vitro, the neuraminidase (NA) of A/WSN/33 (WSN) virus binds and sequesters plasminogen on the cell surface, leading to enhanced cleavage of the viral hemagglutinin. To obtain direct evidence that the plasminogen-binding activity of the NA enhances the pathogenicity of WSN virus, we generated mutant viruses whose NAs lacked plasminogen-binding activity because of a mutation at the C terminus, from Lys to Arg or Leu. In the presence of trypsin, these mutant viruses replicated similarly to wild-type virus in cell culture. By contrast, in the presence of plasminogen, the mutant viruses failed to undergo multiple cycles of replication while the wild-type virus grew normally. The mutant viruses showed attenuated growth in mice and failed to grow at all in the brain. Furthermore, another mutant WSN virus, possessing an NA with a glycosylation site at position 130 (146 in N2 numbering), leading to the loss of neurovirulence, failed to grow in cell culture in the presence of plasminogen. We conclude that the plasminogen-binding activity of the WSN NA determines its pathogenicity in mice.Influenza A viruses possess two virion surface glycoproteins, a hemagglutinin (HA) and a neuraminidase (NA). The HA binds to cell surface receptors and mediates fusion between the endosomal membrane and the viral envelope. The latter event requires cleavage of the HA into HA1 and HA2 subunits, thereby exposing the N-terminal hydrophobic region, which is thought to interact with the host membrane and trigger membrane fusion (32). Thus, influenza A viruses cannot infect host cells unless the HA is proteolytically cleaved (14,15).Although the virulence of influenza A viruses is controlled polygenically, the HA plays a pivotal role in determining the severity of infection in avian strains (8,11,26). The HA cleavage site sequences in virulent and avirulent avian influenza viruses differ; the former possess a series of basic amino acids at this site, while the latter do not (10, 13). The ubiquitous host proteases furin and PC6, which specifically recognize these multiple basic residues, cleave the HAs of virulent viruses, leading to systemic infection (12,27). By contrast, the HAs of avirulent viruses are not cleaved by these proteases because they lack the requisite series of basic residues at their cleavage sites. Instead, they are susceptible to proteases that are presumably localized in the respiratory and/or intestinal tract, thus leading to localized viral infection.All mammalian influenza viruses, excluding equine H7N7 viruses, have a single Arg residue at the HA cleavage site. Thus, the HAs cannot be cleaved by ubiquitous furin or PC6 protease, resulting in a localized infection. However, a mouseadapted human isolate, A/WSN/33 (WSN; H1N1), which is recognized as a neurovirulent strain, causes systemic infection when inoculated intranasally into mice (3). Studies with WSN-A/Hong Kong/68 (H3N2) reassortant viruses indicated that the NA gene determines WSN neurovirulence in mice by facilitating HA cleavage (24). Only a si...

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“…At sites of MTB infection, in a milieu rich in inflammatory cytokines and MTB, and characterized by the presence of immature mononuclear phagocytes [12], uPAR expression in fact is increased (Z. Toossi, unpublished data). However, it has to be noticed that at sites of MTB infection, the activation of LTGFβ1 by plasmin may occur in part through direct binding and the activation of plasminogen by MTB itself [28].…”

Section: Discussionmentioning

confidence: 99%

Bioactivation of Latent Transforming Growth Factor β1 by Mycobacterium tuberculosis in Human Mononuclear Phagocytes

Aung

Johnson

et al. 2005

Scand J Immunol

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Biologically active transforming growth factor beta 1 (TGFb1) has been identified at sites of Mycobacterium tuberculosis (MTB) infection in the lung; however, the underlying mechanism(s) for its activation is not clear. Here using an enzyme-linked immunospot assay for TGFb1, we show that human blood monocytes (MN) and alveolar macrophages (AM) produce bioactive TGFb1 upon stimulation by MTB. However, only MTB-stimulated MN increased TGFb1 production on a per cell basis. The frequency of TGFb1-producing MN was reduced by an inhibitor of plasmin, bdellin, indicating a role for plasmin pathways in the bioactivation of cytokine. The expression of urokinase plasminogen activator receptor (uPAR) mRNA and both surface and soluble uPAR (CD87) was increased in MTB-activated MN. However, antibody neutralization of uPAR suppressed bioactive TGFb1 in MN alone. Thus, the more immature MN, which are continuously recruited to the lung during tuberculosis (TB), have a higher capacity to bioactivate TGFb1 by expression of components of the plasmin pathway. Excess production and bioactivation of TGFb1 at sites of MTB infection may undermine host immune responses during TB.

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Binding and Activation of Human Plasminogen by Mycobacterium tuberculosis

Cited by 24 publications

References 29 publications

The Lack of Binding of VEK-30, an Internal Peptide from the Group A Streptococcal M-like Protein, PAM, to Murine Plasminogen Is due to Two Amino Acid Replacements in the Plasminogen Kringle-2 Domain

The Lack of Binding of VEK-30, an Internal Peptide from the Group A Streptococcal M-like Protein, PAM, to Murine Plasminogen Is due to Two Amino Acid Replacements in the Plasminogen Kringle-2 Domain

Plasminogen-Binding Activity of Neuraminidase Determines the Pathogenicity of Influenza A Virus

Bioactivation of Latent Transforming Growth Factor β1 by Mycobacterium tuberculosis in Human Mononuclear Phagocytes

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