Externalized Glycolytic Enzymes Are Novel, Conserved, and Early Biomarkers of Apoptosis

Ucker, David S.; Jain, Mohit Raja; Pattabiraman, Goutham; Palasiewicz, Karol; Birge, Raymond B.; Li, Hong

doi:10.1074/jbc.m111.314971

Cited by 47 publications

(52 citation statements)

References 100 publications

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“…10,11 The cell surface determinant(s) involved in initiating IAI are not masked by annexin V, rather, they are protease-sensitive. 12 In addition, they are evolutionarily conserved, resident in all cells prior to cell death, and become surface-exposed (and susceptible to proteolytic digestion) during the process of apoptosis. We have referred to these characteristics as SUPER (surface-exposed (during apoptotic cell death), ubiquitously expressed (on all apoptotic cells), proteasesensitive, evolutionarily conserved, and resident normally in viable cells).…”

Section: Open Questionsmentioning

confidence: 99%

“…We have referred to these characteristics as SUPER (surface-exposed (during apoptotic cell death), ubiquitously expressed (on all apoptotic cells), proteasesensitive, evolutionarily conserved, and resident normally in viable cells). 12 (Subsequent responses, including the production of anti-inflammatory factors and cytokines (such as transforming growth factor-β; TGFβ), which may maintain and/or enhance IAI, are linked to PS-dependent apoptotic cell internalization [13][14][15] . )…”

Section: Open Questionsmentioning

confidence: 99%

“…[26][27][28][29][30][31][32][33] Independent studies also have implicated externalized α-enolase and GAPDH on mammalian and pathogen surfaces as sites for plasminogen binding and subsequent activation by host or pathogen activities, [26][27][28]30,31,[34][35][36] and we have demonstrated that externalized glycolytic enzymes on the apoptotic cell surface, including α-enolase, also are sites for plasminogen binding. 12 Although enhanced virulence has been attributed to the presumptive augmentation in mobility through matrix or fibrin clots associated with localized plasminogen activation following binding on the pathogen surface, 37,38 no compelling physiological rationale exists for plasminogen binding on non-invasive bacteria and apoptotic cells. We have argued that the exposure of glycolytic enzymes on microorganisms reflects an exploitation of IAI through apoptotic mimicry, and that consequent immune suppression facilitates pathogenesis, as well as commensalism.…”

Section: Box 1 the Repertoire Of Innate Apoptotic Immunity Early Tranmentioning

confidence: 99%

“…We have argued that the exposure of glycolytic enzymes on microorganisms reflects an exploitation of IAI through apoptotic mimicry, and that consequent immune suppression facilitates pathogenesis, as well as commensalism. 12 Some microbial pathogens, such as the food-borne bacterium Listeria monocytogenes, 39 trigger host cell death directly. Although several insightful studies have implicated a functionally significant role for the involvement of apoptotic cells in instances of pathogenesis such as these, 40,41 the broader complexity and diversity of apoptotic and apoptoticlike events involved in enhancing microbial pathogenesis has not previously been appreciated fully.…”

Section: Box 1 the Repertoire Of Innate Apoptotic Immunity Early Tranmentioning

confidence: 99%

“…The externalization of these glycolytic enzyme molecules is a common early event during the process of apoptotic cell death. These externalized molecules fulfill SUPER criteria and are linked to the triggering of IAI (adapted from Ucker et al 12 ) facilitate pathogenicity. Mice lacking lymphocytes (and consequent apoptotic lymphocytes induced during infection) were found to be less susceptible to Listeria monocytogenes infection than were lymphocyte-replete, wild-type mice.…”

Section: Apoptotic Subversionmentioning

confidence: 99%

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Exploiting death: apoptotic immunity in microbial pathogenesis

Ucker

2016

Cell Death Differ

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Innate immunity typically is responsible for initial host responses against infections. Independently, nucleated cells that die normally as part of the physiological process of homeostasis in mammals (including humans) suppress immunity. Specifically, the physiological process of cell death (apoptosis) generates cells that are recognized specifically by viable cells of all types and elicit a profound transient suppression of host immunity (termed 'innate apoptotic immunity' (IAI)). IAI appears to be important normally for the maintenance of self-tolerance and for the resolution of inflammation. In addition, pathogens are able to take advantage of IAI through a variety of distinct mechanisms, to enable their proliferation within the host and enhance pathogenicity. For example, the protist pathogen Leishmania amazonensis, at its infective stage, mimics apoptotic cells by expressing apoptotic-like protein determinants on the cell surface, triggering immunosuppression directly. In contrast, the pathogenic bacterium Listeria monocytogenes triggers cell death in host lymphocytes, relying on those apoptotic cells to suppress host immune control and facilitate bacterial expansion. Finally, although the inhibition of apoptotic cell death is a common attribute of many viruses which facilitates their extended replication, it is clear that adenoviruses also reprogram the non-apoptotic dead cells that arise subsequently to manifest apoptotic-like immunosuppressive properties. These three instances represent diverse strategies used by microbial pathogens to exploit IAI, focusing attention on the potency of this facet of host immune control. Further examination of these cases will be revealing both of varied mechanisms of pathogenesis and the processes involved in IAI control.

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Section: Open Questionsmentioning

confidence: 99%

Section: Open Questionsmentioning

confidence: 99%

Section: Box 1 the Repertoire Of Innate Apoptotic Immunity Early Tranmentioning

confidence: 99%

Section: Box 1 the Repertoire Of Innate Apoptotic Immunity Early Tranmentioning

confidence: 99%

Section: Apoptotic Subversionmentioning

confidence: 99%

See 3 more Smart Citations

Exploiting death: apoptotic immunity in microbial pathogenesis

Ucker

2016

Cell Death Differ

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RAC1 inhibition reverses cisplatin resistance in esophageal squamous cell carcinoma and induces downregulation of glycolytic enzymes

Zeng

Zheng

et al. 2019

Molecular Oncology

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Development of chemoresistance remains a major challenge in treating esophageal squamous cell carcinoma (ESCC) patients despite treatment advances. However, the role of RAC1 in chemoresistance of ESCC and the underlying mechanisms remain largely unknown. In this study, we found that higher levels of RAC1 expression were associated with poorer prognosis in ESCC patients. Enhanced RAC1 expression increased cell proliferation, migration, and chemoresistance in vitro . Combination therapy using RAC1 inhibitor EHop‐016 and cisplatin significantly promoted cell viability inhibition, G2/M phase cycle arrest, and apoptosis when compared to each monotherapy. Mechanistically, glycolysis was significantly downregulated in the RAC1 inhibitor monotherapy group and the combination group via inhibiting AKT/FOXO3a signaling when compared to the control group. Moreover, the silencing of RAC1 inhibited AKT/FOXO3a signaling and cell glycolysis while the upregulation of RAC1 produced an opposite effect. In murine xenograft models, the tumor volume and the expression of glycolytic enzymes were significantly reduced in combination therapy when compared to each monotherapy group. Overall, our study demonstrates that targeting RAC1 with an inhibitor overcomes cisplatin resistance in ESCC by suppressing glycolytic enzymes, which provides a promising strategy for treatment of ESCC in clinical practice.

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Exploring the interaction between Mycobacterium tuberculosis enolase and human plasminogen using computational methods and experimental techniques

Rahi

Dhiman

Singh

et al. 2017

J of Cellular Biochemistry

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Surface localized microbial enolases' binding with human plasminogen has been increasingly proven to have an important role in initial infection cycle of several human pathogens. Likewise, surface localized Mycobacterium tuberculosis (Mtb) enolase also binds to human plasminogen, and this interaction may entail crucial consequences for granuloma stability. The current study is the first attempt to explore the plasminogen interacting residues of enolase from Mtb. Beginning with the structural modeling of Mtb enolase, the binding pose of Mtb enolase and human plasminogen was predicted using protein-protein docking simulations. The binding pose revealed the interface region with interacting residues and molecular interactions. Next, the interacting residues were refined and ranked by using various criteria. Finally, the selected interacting residues were tested experimentally for their involvement in plasminogen binding. The two consecutive lysine residues, Lys-193 and Lys-194, turned out to be active residues for plasminogen binding. These residues when substituted for alanine along with the most active residue Lys-429, that is, the triple mutant (K193A + K194A + K429A) Mtb enolase, exhibited 40% reduction in plasminogen binding. It is worth noting that Mtb enolase lost nearly half of the plasminogen binding activity with only three simultaneous substitutions, without any significant secondary structure perturbation. Further, the sequence comparison between Mtb and human enolase isoforms suggests the possibility of selective targeting of Mtb enolase to obstruct binding of human plasminogen.

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Externalized Glycolytic Enzymes Are Novel, Conserved, and Early Biomarkers of Apoptosis

Cited by 47 publications

References 100 publications

Exploiting death: apoptotic immunity in microbial pathogenesis

Exploiting death: apoptotic immunity in microbial pathogenesis

RAC1 inhibition reverses cisplatin resistance in esophageal squamous cell carcinoma and induces downregulation of glycolytic enzymes

Exploring the interaction between Mycobacterium tuberculosis enolase and human plasminogen using computational methods and experimental techniques

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