ZEA-induced autophagy in TM4 cells was mediated by the release of Ca2+ activates CaMKKβ-AMPK signaling pathway in the endoplasmic reticulum

Feng, Na; Wang, Bingjie; Cai, Peirong; Zheng, Wanglong; Zou, Hui; Gu, Jianhong; Yuan, Yan; Liu, Zongping; Bian, Jianchun

doi:10.1016/j.toxlet.2020.01.010

Cited by 22 publications

(12 citation statements)

References 47 publications

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“…Our results showed that ZEA could increase the concentration of intracellular Ca 2+ in a dose-dependent manner, and the decrease in cell viability induced by ZEA can be effectively alleviated by adding the intracellular Ca integrator BAPTA-AM. These results show that a Ca 2+ overload in TM4 cells may be caused by the release of intracellular Ca stores by ZEA, which is consistent with the results of our previous study [27]. Our study found that BAPTA-AM combined with ZEA can reverse the upregulation of LC3-II and p62 proteins induced by ZEA, indicating that the increase in intracellular Ca may be involved in autophagy induced by ZEA.…”

Section: Discussionsupporting

confidence: 93%

“…Researchers believe that Ca 2+ has a positive and negative regulatory effect on autophagy under normal and stress conditions, respectively. Studies have shown that Ca 2+ promotes autophagy through a variety of pathways, such as IP3R and beclin1 pathway and calmodulin-dependent protein kinase beta CaMKKβ-AMPK-mTOR pathway [25][26][27]. It is also believed that Ca 2+ may inhibit autophagy through IP3R, BECLIN1-Bcl-2 complex, and AMPK-mTOR pathways [28,29].…”

Section: Introductionmentioning

confidence: 99%

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Zearalenone Exposure Disrupts Blood–Testis Barrier Integrity through Excessive Ca2+-Mediated Autophagy

She

Feng

Zheng

et al. 2021

Toxins

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Zearalenone (ZEA), a common mycotoxin in grains and animal feeds, has been associated with male reproductive disorders. However, the potential toxicity mechanism of ZEA is not fully understood. In this study, in vivo and in vitro models were used to explore the effects of ZEA on the blood–testis barrier (BTB) and related molecular mechanisms. First, male BALB/C mice were administered ZEA orally (40 mg/kg·bw) for 5–7 d. Sperm motility, testicular morphology, and expressions of BTB junction proteins and autophagy-related proteins were evaluated. In addition, TM4 cells (mouse Sertoli cells line) were used to delineate the molecular mechanisms that mediate the effects of ZEA on BTB. Our results demonstrated that ZEA exposure induced severe testicular damage in histomorphology and an ultrastructural, time-dependent decrease in the expression of blood–testis barrier junction-related proteins, accompanied by an increase in the expression of autophagy-related proteins. Additionally, similar to the in vitro results, the dose-dependent treatment of ZEA increased the level of cytoplasmic Ca2+ and the levels of the autophagy markers LC3-II and p62, in conjunction with a decrease in the BTB junction proteins occludin, claudin-11, and Cx43, with the dislocation of the gap junction protein Cx43. Meanwhile, inhibition of autophagy by CQ and 3-MA or inhibition of cytoplasmic Ca2+ by BAPTA-AM was sufficient to reduce the effects of ZEA on the TM4 cell BTB. To summarize, this study emphasizes the role of Ca2+-mediated autophagy in ZEA-induced BTB destruction, which deepens our understanding of the molecular mechanism of ZEA-induced male reproductive disorders.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Zearalenone Exposure Disrupts Blood–Testis Barrier Integrity through Excessive Ca2+-Mediated Autophagy

She

Feng

Zheng

et al. 2021

Toxins

Self Cite

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“…These findings are fairly consistent with those of the recent study showing that compound K, a major metabolite of ginsenosides, induces apoptosis by activating ER Ca 2+ channels known as ryanodine receptors to release ER Ca 2+ in human lung cancer cells, the A549, and SK-MES-1 cell lines [40]. Although ZEN has also been reported to increase cytosolic Ca 2+ level by inducing ER stress in TM4 cells [41], ovarian cells from pre-pubertal bitches [42] and lymphocytes of chickens [24], our data do not support the involvement of ER stress in ZEN-induced apoptosis. At present, the reason for these inconsistencies has not been determined, but they may be attributable to the different cell types used in our study; BAECs versus TM4 and ovarian cells.…”

Section: Discussionsupporting

confidence: 92%

Zearalenone Induces Endothelial Cell Apoptosis through Activation of a Cytosolic Ca2+/ERK1/2/p53/Caspase 3 Signaling Pathway

Lee

2021

Toxins

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Zearalenone (ZEN) is a mycotoxin that has been reported to damage various types of cells/tissues, yet its effects on endothelial cells (ECs) have never been investigated. Therefore, this study investigates the potential effects of ZEN using bovine aortic ECs (BAECs). In this study, we found that ZEN induced apoptosis of BAECs through increased cleavage of caspase 3 and poly ADP-ribose polymerase (PARP). ZEN also increased phosphorylation of ERK1/2 and p53, and treatment with the ERK1/2 or p53 inhibitor reversed ZEN-induced EC apoptosis. Transfection of BAECs with small interfering RNA against ERK1/2 or p53 revealed ERK1/2 as an upstream target of p53 in ZEN-stimulated apoptosis. ZEN increased the production of reactive oxygen species (ROS), yet treatment with the antioxidant did not prevent EC apoptosis. Similarly, blocking of estrogen receptors by specific inhibitors also did not prevent ZEN-induced apoptosis. Finally, chelation of cytosolic calcium (Ca2+) using BAPTA-AM or inhibition of endoplasmic reticulum (ER) Ca2+ channel using 2-APB reversed ZEN-induced EC apoptosis, but not by inhibiting ER stress using 4-PBA. Together, our findings demonstrate that ZEN induces EC apoptosis through an ERK1/2/p53/caspase 3 signaling pathway activated by Ca2+ release from the ER, and this pathway is independent of ROS production and estrogen receptor activation.

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“…HA induces Ca 2+ elevation in cells and may increase the activity of Ca 2+ -associated signaling pathways (Singleton and Bourguignon, 2002). For example, an increase of cytoplasmic Ca 2+ levels can induce autophagy through CaMKKβ and AMPK pathways (Feng et al, 2020; Green et al, 2011). To test whether HA and CD44 interactions elevate intracellular Ca 2+ ([Ca 2+ ] i ) levels and induce autophagy by Ca 2+ -mediated activation of CaMKKβ and AMPK pathways, we incubated host cells with Cn cells, HA, naked beads, or HA-coated beads, and then visualized [Ca 2+ ]i levels and activation of CaMKKβ-AMPK pathways in the treated cells.…”

Section: Resultsmentioning

confidence: 99%

“…Activation of AMPK can induce autophagy via direct phosphorylation of ULK1 (Egan et al, 2011; Kim et al, 2011; Zhao and Klionsky, 2011). Previous observations showed that HA interactions with CD44 induces Ca 2+ elevation in cells (Singleton and Bourguignon, 2002), and that increases in cytoplasmic Ca 2+ concentrations induce autophagy through activation of CaMKKβ and AMPK pathways (Feng et al, 2020; Green et al, 2011). Similarly, our findings demonstrate that infection by Cn recruits host cell CD44 to CnCVs, induces intracellular Ca 2+ -flux in the infected host cells, activates CaMKKβ and AMPK, and recruits AIC components to forming or nascent CnCVs.…”

Section: Discussionmentioning

confidence: 99%

Interactions between fungal hyaluronic acid and host CD44 promote internalization by recruiting host autophagy proteins to forming phagosomes

Ding

Pandey

Feng

et al. 2020

Preprint

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2Phagocytosis and autophagy play critical roles in immune defense. Cryptococcus neoformans (Cn), 3 a fungal pathogen that causes fatal infection, subverts the host autophagy initiation complex (AIC) 4 and its upstream regulatory proteins, to promote its phagocytosis and intracellular parasitism of 5 host cells. The mechanisms by which the pathogen engages host AIC proteins remain obscure. 6Here, we show that the recruitment of host AIC proteins to forming phagosomes is dependent 7 upon the activity of CD44, a host cell surface receptor that engages fungal hyaluronic acid (HA). 8This interaction elevates intracellular Ca 2+ concentrations and activates CaMKKb and its 9 downstream target AMPKα, which results in activation of ULK1 and the recruitment of AIC 10 components. Moreover, we demonstrate that HA-coated beads efficiently recruit AIC components 11 to phagosomes. Taken together, these findings show that fungal HA plays a critical role in 12 directing the internalization and productive intracellular membrane trafficking of a fungal 13 pathogen of global importance. 14 15 16 Ganley, I.G., Lam, D.H., Wang, J., Ding, X., Chen, S., and Jiang, X. (2009). ULK1· ATG13· FIP200 complex 1 mediates mTOR signaling and is essential for autophagy.

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ZEA-induced autophagy in TM4 cells was mediated by the release of Ca2+ activates CaMKKβ-AMPK signaling pathway in the endoplasmic reticulum

Cited by 22 publications

References 47 publications

Zearalenone Exposure Disrupts Blood–Testis Barrier Integrity through Excessive Ca2+-Mediated Autophagy

Zearalenone Exposure Disrupts Blood–Testis Barrier Integrity through Excessive Ca2+-Mediated Autophagy

Zearalenone Induces Endothelial Cell Apoptosis through Activation of a Cytosolic Ca2+/ERK1/2/p53/Caspase 3 Signaling Pathway

Interactions between fungal hyaluronic acid and host CD44 promote internalization by recruiting host autophagy proteins to forming phagosomes

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