New insights into the structure and function of the plasminogen/plasmin system

Law, Ruby H. P.; Abu-ssaydeh, Diana; Whisstock, James C.

doi:10.1016/j.sbi.2013.10.006

Cited by 123 publications

(119 citation statements)

References 46 publications

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“…For years, Pg has been thought to be primarily a liver-derived protein [25], then the question is how widely Pg may be expressed in other organs, including the brain. Currently, there is an ample body of literature regarding the involvement of Pg/ Pm system in CNS development, normal neural functioning as well as neurologic disorders [1,2,5]. Our data expand evidences that rat brain cells are able to produce Pg and are in accordance with the previous reports indicating that Pg is expressed by specific populations of hippocampal, cortical and hypothalamic neurons in murine brain [13,26].…”

Section: Fig 2 Representative Fluorescence Micrographs Of Plasminogsupporting

confidence: 91%

“…Pg/Pm system has rather ubiquitous nature in an organism. The relative abundance of Pg as well as PAs and their cell receptors in different tissues indicates a potential regulatory role of this system in the extracellular events requiring proteolysis or controlling cellular activity, beyond the role of these proteins in the fibrinolytic pathway [1]. Substantial evidences have established that proteins of Pg/Pm system are responsible for many important functions within a brain [2].…”

Section: The Purpose Of the Present Study Was To Examine The Plasminomentioning

confidence: 99%

“…It has been also shown that Pg displays remarkab le structural and functional plasticity, and this determines its physiological function far beyond the fibrinolytic system [1]. In a brain, Pg in concert with its activators, has important functions being involved in neurite outgrowth, neuronal migration, the maintenance of the long-term potentiation (LTP), ocular dominance plasticity, anxiety-like behavior, neuronal degeneration, and blood supply [27].…”

Section: Fig 2 Representative Fluorescence Micrographs Of Plasminogmentioning

confidence: 99%

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Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation

Tykhomyrov¹,

Nedzvetsky²,

Ağca³

et al. 2017

Ukr.Biochem.J.

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Section: Fig 2 Representative Fluorescence Micrographs Of Plasminogsupporting

confidence: 91%

Section: The Purpose Of the Present Study Was To Examine The Plasminomentioning

confidence: 99%

Section: Fig 2 Representative Fluorescence Micrographs Of Plasminogmentioning

confidence: 99%

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Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation

Tykhomyrov¹,

Nedzvetsky²,

Ağca³

et al. 2017

Ukr.Biochem.J.

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“…Plasmin is a serine protease that is able to cleave extracellular matrix components and complement proteins, such as C3b and C5 (Barthel et al, 2012a;Law et al, 2013). Our group has shown that PLG bound to leptospires can be activated into plasmin, cleaving C3b and IgG, thus decreasing their deposition on the bacterial surface (Vieira et al, 2011).…”

Section: Cleavage Of C3b and C4b By Plasmin Bound To Lsa23mentioning

confidence: 99%

Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation

et al. 2016

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It has been reported that pathogenic Leptospira are resistant to normal human serum (NHS) due to their ability to evade the complement immune system by interacting with factor H (FH) and C4b-binding protein (C4BP) regulators. Moreover, plasmin generation on the leptospiral surface diminishes C3b and IgG deposition, decreasing opsonophagocytosis by immune competent cells. We have previously reported that Lsa23 (LIC11360) is a multipurpose protein capable of binding purified extracellular matrix molecules, FH, C4BP and plasminogen (PLG)/plasmin in the presence of PLG activators. In this work, we provide further evidence that Lsa23 is located at the bacterial surface by using immunofluorescence microscopy. We show that Lsa23 has the ability to acquire FH, C4BP and PLG from NHS, and use these interactions to evade innate immunity. The binding with the complement regulators FH and C4BP preserves factor I (FI) activity, leading to C3b and C4b degradation products, respectively. C3b and C4b alpha-chain cleavage was also observed when Lsa23 bound to PLG generating plasmin, an effect blocked by the protease inhibitor aprotinin. Lsa23 also inhibited lytic activity by NHS mediated by both classical and alternative complement pathways. Thus, Lsa23 has the ability to block both pathways of the complement system, and may help pathogenic Leptospira to escape complement-mediated clearance in human hosts. Indeed, NHS treated with Lsa23 confers a partial serum resistance phenotype to Leptospira biflexa, whereas blocking this protein with anti-Lsa23 renders pathogenic L. interrogans more susceptible to complement-mediated killing. Thus, Lsa23 is a multifunctional protein involved in many pathways, featuring C4b cleavage by plasmin, knowledge that may help in the development of preventive approaches to intervene with human complement escape by this versatile pathogen.

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“…Using streptococcal supernatant from an isogenic ska knockout strain, we found that SK is an important component activating the contact system independently from a bacterial surface through the generation of plasmin. Many invasive pathogens exploit plasmin as a virulence factor to degrade fibrin clots, overcome tissue barriers, and evade peptide-derived host immune defenses (34,35). Under normal conditions, soluble plasmin is immediately inhibited by ␣2-antiplasmin (6,22,32,36); however, the SK-plasmin complex is protected from this inhibitor and promotes uncontrolled plasmin activity.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase

et al. 2015

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Severe invasive infectious diseases remain a major and life-threatening health problem. In serious cases, a systemic activation of the coagulation cascade is a critical complication that is associated with high mortality rates. We report here that streptokinase, a group A streptococcal plasminogen activator, triggers the activation of the human contact system. Activation of contact system factors at the surface of the Streptococcus pyogenes serotype M49 is dependent on streptokinase and plasminogen. Our results also show that secreted streptokinase is an efficient contact system activator, independent from a contact surface. This results in the processing of high-molecular-weight kininogen and the release of bradykinin, a potent vascular mediator. We further investigated whether the ability of 50 different clinical S. pyogenes isolates to activate the contact system is associated with an invasive phenotype. The data reveal that isolates from invasive infections trigger an activation of the contact system more potently than strains isolated from noninvasive infections. The present study gives new insights into the mechanisms by which S. pyogenes triggers the human contact system and stresses the function of soluble and surface located plasmin exploited as a group A streptococcal virulence factor through the action of streptokinase.

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New insights into the structure and function of the plasminogen/plasmin system

Cited by 123 publications

References 46 publications

Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation

Plasminogen and its fragments in rat brain: a plausible role for astrocytes in angiostatin generation

Leptospira interrogans Lsa23 protein recruits plasminogen, factor H and C4BP from normal human serum and mediates C3b and C4b degradation

Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase

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