Enzymatically active apurinic/apyrimidinic endodeoxyribonuclease 1 is released by mammalian cells through exosomes

Mangiapane, Giovanna; Parolini, Isabella; Conte, Kristel; Malfatti, Matilde Clarissa; Corsi, Jessica; Sanchez, Massimo; Pietrantoni, Agostina; D’Agostino, Vito; Tell, Gianluca

doi:10.1016/j.jbc.2021.100569

Cited by 22 publications

(31 citation statements)

References 76 publications

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“…In fact, its concentration in the serum of hepatocellular carcinoma and nonsmall cell lung cancer patients is increased as compared with healthy controls [67,77]. APE1 has been found to be secreted in active form and through exosomes in response to genotoxic treatments [78].…”

Section: The N-terminal Tail and Ape1 Subcellular Localizationmentioning

confidence: 99%

Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain

López

Rodríguez

Bañuelos

2021

IJMS

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APE1 (DNA (apurinic/apyrimidinic site) endonuclease 1) is a key enzyme of one of the major DNA repair routes, the BER (base excision repair) pathway. APE1 fulfils additional functions, acting as a redox regulator of transcription factors and taking part in RNA metabolism. The mechanisms regulating APE1 are still being deciphered. Structurally, human APE1 consists of a well-characterized globular catalytic domain responsible for its endonuclease activity, preceded by a conformationally flexible N-terminal extension, acquired along evolution. This N-terminal tail appears to play a prominent role in the modulation of APE1 and probably in BER coordination. Thus, it is primarily involved in mediating APE1 localization, post-translational modifications, and protein–protein interactions, with all three factors jointly contributing to regulate the enzyme. In this review, recent insights on the regulatory role of the N-terminal region in several aspects of APE1 function are covered. In particular, interaction of this region with nucleophosmin (NPM1) might modulate certain APE1 activities, representing a paradigmatic example of the interconnection between various regulatory factors.

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Section: The N-terminal Tail and Ape1 Subcellular Localizationmentioning

confidence: 99%

Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain

López

Rodríguez

Bañuelos

2021

IJMS

View full text Add to dashboard Cite

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“…In triple-negative breast cancer cells, acetylated APE1 initiates apoptosis by binding to the receptor for advanced glycation end products, resulting in significant decrease in cell viability (142). Some studies have demonstrated that secreted APE1 retains redox function (140) and DNA repair activity (136). Mangiapane et al demonstrated that APE1 is secreted through exosomes from several cancer cell lines.…”

Section: Ape1 As a Serologic Biomarkermentioning

confidence: 99%

“…In patients with non-small cell lung cancer, serum APE1 autoantibodies were significantly higher than those in healthy controls, and were closely related to APE1 antigen levels in tumor tissues and peripheral blood ( 135 ). Although significant evidence shows that APE1 is delivered through exosomes in response to genotoxic stresses ( 136 ), a recent study showed the endogenous hormone 17β-estradiol (E2) significantly increased APE1 secretion in plasma of ovariectomized mice ( 137 ). These data suggest that APE1 secretion may also be a natural response in cellular physiology that does not necessarily depend on stress.…”

Section: Ape1 As a Serologic Biomarkermentioning

confidence: 99%

APE1/Ref-1 Role in Inflammation and Immune Response

et al. 2022

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Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme that is essential for maintaining cellular homeostasis. APE1 is the major apurinic/apyrimidinic endonuclease in the base excision repair pathway and acts as a redox-dependent regulator of several transcription factors, including NF-κB, AP-1, HIF-1α, and STAT3. These functions render APE1 vital to regulating cell signaling, senescence, and inflammatory pathways. In addition to regulating cytokine and chemokine expression through activation of redox sensitive transcription factors, APE1 participates in other critical processes in the immune response, including production of reactive oxygen species and class switch recombination. Furthermore, through participation in active chromatin demethylation, the repair function of APE1 also regulates transcription of some genes, including cytokines such as TNFα. The multiple functions of APE1 make it an essential regulator of the pathogenesis of several diseases, including cancer and neurological disorders. Therefore, APE1 inhibitors have therapeutic potential. APE1 is highly expressed in the central nervous system (CNS) and participates in tissue homeostasis, and its roles in neurodegenerative and neuroinflammatory diseases have been elucidated. This review discusses known roles of APE1 in innate and adaptive immunity, especially in the CNS, recent evidence of a role in the extracellular environment, and the therapeutic potential of APE1 inhibitors in infectious/immune diseases.

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“…Extracellular APE1/ Ref-1 is known to have its own function and can affect surrounding and distant cells. Enzymatically active APE1/Ref-1 protein that functions as an endonuclease is secreted in response to genotoxic stress [9]. Secretory APE1/Ref-1 has been reported to have a role in the inhibition of vascular inflammation via thiol-disulfide exchange in the tumor necrosis factor (TNF) receptor [10].…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms of APE1/Ref-1 secretion have not yet been fully elucidated. Some reports on the pathway of APE1/Ref-1 secretion suggested that it may be secreted via exosomes [9,12,15] or the ATP-binding cassette transporter [16].…”

Section: Introductionmentioning

confidence: 99%

17β-Estradiol Increases APE1/Ref-1 Secretion in Vascular Endothelial Cells and Ovariectomized Mice: Involvement of Calcium-Dependent Exosome Pathway

et al. 2021

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Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that can be secreted, and recently suggested as new biomarker for vascular inflammation. However, the endogenous hormones for APE1/Ref-1 secretion and its underlying mechanisms are not defined. Here, the effect of twelve endogenous hormones on APE1/Ref-1 secretion was screened in cultured vascular endothelial cells. The endogenous hormones that significantly increased APE1/Ref-1 secretion was 17β-estradiol (E2), 5?-dihydrotestosterone, progesterone, insulin, and insulin-like growth factor. The most potent hormone inducing APE1/Ref-1 secretion was E2, which in cultured endothelial cells, E2 for 24h increased APE1/Ref-1 secretion level of 4.56 ± 1.16 ng/mL, compared to a basal secretion level of 0.09 ± 0.02 ng/mL. Among the estrogens, only E2 increased APE1/Ref-1 secretion, not estrone and estriol. Blood APE1/Ref-1 concentrations decreased in ovariectomized (OVX) mice but were significantly increased by the replacement of E2 (0.39 ± 0.09 ng/mL for OVX vs. 4.67 ± 0.53 ng/mL for OVX + E2). E2-induced APE1/Ref-1secretion was remarkably suppressed by the estrogen receptor (ER) blocker fulvestrant and intracellular Ca2+ chelator 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), suggesting E2-induced APE1/Ref-1 secretion was dependent on ER and intracellular calcium. E2-induced APE1/Ref-1 secretion was significantly inhibited by exosome inhibitor GW4869. Furthermore, APE1/Ref-1 level in CD63-positive exosome were increased by E2. Finally, fluorescence imaging data showed that APE1/Ref-1 co-localized with CD63-labled exosome in the cytoplasm of cells upon E2 treatment. Taken together, E2 was the most potent hormone for APE1/Ref-1 secretion, which appeared to occur through exosomes that were dependent on ER and intracellular Ca2+. Furthermore, hormonal effects should be considered when analyzing biomarkers for vascular inflammation.

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Enzymatically active apurinic/apyrimidinic endodeoxyribonuclease 1 is released by mammalian cells through exosomes

Cited by 22 publications

References 76 publications

Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain

Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain

APE1/Ref-1 Role in Inflammation and Immune Response

17β-Estradiol Increases APE1/Ref-1 Secretion in Vascular Endothelial Cells and Ovariectomized Mice: Involvement of Calcium-Dependent Exosome Pathway

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