Entamoeba histolytica Cysteine Proteinase 5 Binds Integrin on Colonic Cells and Stimulates NFκB-mediated Pro-inflammatory Responses

Hou, Yongzhong; Mortimer, Leanne; Chadee, Kris

doi:10.1074/jbc.m109.066035

Cited by 91 publications

(93 citation statements)

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“…The cysteine proteinase A5 (CP-A5) interacts directly with integrins at the surface of human colon epithelial cells and induces the secretion of pro-inflammatory cytokines (including TNF-a and IL-1b; ref. 8). Thus, trophozoites epigenetically silenced for CP-A5 (that is, CP-A5 negative) fail to trigger a host inflammatory response or induce the collagen remodelling required for invasion of the lamina propria 3,4 .…”

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The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue

et al. 2014

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Intestinal invasion by the protozoan parasite Entamoeba histolytica is characterized by remodelling of the extracellular matrix (ECM). The parasite cysteine proteinase A5 (CP-A5) is thought to cooperate with human matrix metalloproteinases (MMPs) involved in ECM degradation. Here, we investigate the role CP-A5 plays in the regulation of MMPs upon mucosal invasion. We use human colon explants to determine whether CP-A5 activates human MMPs. Inhibition of the MMPs' proteolytic activities abolishes remodelling of the fibrillar collagen structure and prevents trophozoite invasion of the mucosa. In the presence of trophozoites, MMPs-1 and -3 are overexpressed and are associated with fibrillar collagen remodelling. In vitro, CP-A5 performs the catalytic cleavage needed to activate pro-MMP-3, which in turn activates pro-MMP-1. Ex vivo, incubation with recombinant CP-A5 was enough to rescue CP-A5-defective trophozoites. Our results suggest that MMP-3 and/or CP-A5 inhibitors may be of value in further studies aiming to treat intestinal amoebiasis.

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The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue

et al. 2014

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“…Cysteine proteases, among which CP-A5, present at the trophozoite surface or released into the extracellular medium, are implicated in ECM degradation. The pro-form of CP-A5, localized in secreted and surface-bound fractions, contains a RGD sequence that confers to this protein a protease activity-independent additional function in adherence and host cell inflammatory response induction; binding to integrin αvβ3 from colonic enterocyte cells has been found [34], potential receptors on LSEC are not characterized. Activation of vascular endothelial cell G-protein coupled receptors, like the protease-activated receptors (PAR), by pathogen-encoded CPs have been described for several microorganisms, including African trypanosome parasites.…”

Section: Resultsmentioning

confidence: 99%

“…The pro-form of CP-A5 contains an RGD motif for which a role in target cell adherence and triggering of a proinflammatory host cell response has been described [34]. Thus, CP-A5 could play a role as a protease and as a RGDmotif ligand for integrins modifying target cell signalling.…”

Section: European Journal Of Microbiology and Immunology 1 (2011)mentioning

confidence: 99%

New insights into host-pathogen interactions duringEntamoeba histolyticaliver infection

Faust¹,

Markiewicz²,

Santi-Rocca³

et al. 2011

European Journal of Microbiology and Immunology

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Amoebiasis is the third worldwide disease due to a parasite. The causative agent of this disease, the unicellular eukaryote Entamoeba histolytica, causes dysentery and liver abscesses associated with inflammation and human cell death. During liver invasion, before entering the parenchyma, E. histolytica trophozoites are in contact with liver sinusoidal endothelial cells (LSEC). We present data characterizing human LSEC responses to interaction with E. histolytica and identifying amoebic factors involved in the process of cell death in this cell culture model potentially relevant for early steps of hepatic amoebiasis. E. histolytica interferes with host cell adhesion signalling and leads to diminished adhesion and target cell death. Contact with parasites induces disruption of actin stress fibers and focal adhesion complexes. We conclude that interference with LSEC signalling may result from amoeba-triggered changes in the mechanical forces in the vicinity of cells in contact with parasites, sensed and transmitted by focal adhesion complexes. The study highlights for the first time the potential role in the onset of hepatic amoebiasis of the loss of liver endothelium integrity by disturbance of focal adhesion function and adhesion signalling. Among the amoebic factors required for changed LSEC adherence properties we identified the Gal/GalNAC lectin, cysteine proteases and KERP1.

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“…[3][4][5] The IKKs/NFkB pathway is activated by extracellular stimuli such as cytokines, ultraviolet irradiation, free radicals, bacterial or viral antigens and oxidized low density lipoprotein. 3,4 In the absence of persistent upstream stimuli, NFkB transcriptional activity is terminated by the NFkB/IkBa negative feedback loop. 4 The activation of NFkB in immune or stromal cells causes a pro-inflammatory response, and persistent tissue inflammation has been linked to inflammation-associated cancer.…”

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confidence: 99%

“…IKK1 and IKK2 are the catalytic subunits, whereas IKKc serves as a non-enzymatic regulator. [3][4][5] The IKKs/NFkB pathway is activated by extracellular stimuli such as cytokines, ultraviolet irradiation, free radicals, bacterial or viral antigens and oxidized low density lipoprotein. 3,4 In the absence of persistent upstream stimuli, NFkB transcriptional activity is terminated by the NFkB/IkBa negative feedback loop.…”

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confidence: 99%

Ubiquitin-mediated NFκB degradation pathway

You

Shi

et al. 2014

Cell Mol Immunol

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The nuclear factor kB (NFkB) transcription factor plays critical roles in inflammation and immunity. The dysregulation of NFkB is associated with inflammatory and autoimmune diseases and cancer. NFkB activation is negatively regulated by the ubiquitin-dependent proteasomal degradation pathway. In the present review, we discuss recent advances in our understanding of how ubiquitin ligases regulate the NFkB degradation pathway. Keywords: NFkB; ubiquitination; degradation; pathway Nuclear factor kB (NFkB) was identified approximately 20 years ago by Dr David Baltimore as a transcription factor that binds to the intronic enhancer of the kappa light chain gene (the kB site) in B cells. 1 The NFkB family is composed of several members including p50, p52, p65/RelA, c-Rel and RelB and plays a central role in cell growth, inflammation, immunity and apoptosis. NFkB activation is dependent on the stability of the inhibitor IkBa. IkBa stabilizes the NFkB complex so that after its degradation the remaining subunits translocate from the cytoplasm to the nucleus. 2 The phosphorylation of IkBa is catalyzed by IkB kinase (IKK), a complex composed of three subunits: IKKa/IKK1, IKKb/IKK2, and IKKc/NEMO. IKK1 and IKK2 are the catalytic subunits, whereas IKKc serves as a non-enzymatic regulator. [3][4][5] The IKKs/NFkB pathway is activated by extracellular stimuli such as cytokines, ultraviolet irradiation, free radicals, bacterial or viral antigens and oxidized low density lipoprotein. 3,4 In the absence of persistent upstream stimuli, NFkB transcriptional activity is terminated by the NFkB/IkBa negative feedback loop. 4 The activation of NFkB in immune or stromal cells causes a pro-inflammatory response, and persistent tissue inflammation has been linked to inflammation-associated cancer. 6 NFkB activation is negatively regulated by ubiquitin-dependent proteasomal degradation. 7-9 The ubiquitin-proteasome system comprises a ubiquitin-activating enzyme (E1), a ubiquitinconjugating enzyme (E2) and a ubiquitin ligase (E3). Ubiquitin E3 ligases play a critical role in substrate recognition and polyubiquitination by recruiting E2 ubiquitin-conjugating enzymes to specific substrates. 10 SOCS-1 (suppressor of cytokine signaling) is one of the components of the EC 2 S (Elongin BC-CUL2-SOCS-box protein) ubiquitin ligase complex that mediates JAK2 (Janus kinase 2) ubiquitination and degradation. 11,12 Similar to JAK2, NFkB/p65 is also a substrate of the EC 2 S ubiquitin ligase complex in both mice and cancer cells. 13 Pin1 increases NFkB/p65 stability and transactivation, while the loss of Pin1 leads to SOCS-1-mediated p65 ubiquitination and degradation. 13 This offers a new mechanism for NFkBmediated pathogenesis.NFkB is also activated by viral infections. In immunodeficiency virus-1-infected CD4 1 lymphocytes, NFkB activation is terminated by COMMD1 (MURR1), resulting in the inhibition of immunodeficiency virus-1 growth in unstimulated or cytokine-stimulated CD4 1 T cells. 14 This study demonstrated that COMMD1 decreases NFkB transcriptio...

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Entamoeba histolytica Cysteine Proteinase 5 Binds Integrin on Colonic Cells and Stimulates NFκB-mediated Pro-inflammatory Responses

Abstract: The colonic protozoan parasite Entamoeba histolytica (Eh) 2

Cited by 91 publications

References 42 publications

The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue

The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue

New insights into host-pathogen interactions duringEntamoeba histolyticaliver infection

Ubiquitin-mediated NFκB degradation pathway

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