Silica nanoparticles induce unfolded protein reaction mediated apoptosis in spermatocyte cells

Abstract With increasing air pollution, silica nanoparticles (SiNPs), as a main inorganic member of PM2.5, have gained increasing attention to its reproductive toxicity. Most existing studies focused on the acute exposure, while data regarding the chronic effect of SiNPs on reproduction is limited. Therefore, this study was designed to evaluate the chronic toxicity of SiNPs on spermatocyte cells. The cells were continuously exposed to SiNPs for 1, 10, 20 and 30 generations at dose of 5 μg/ml SiNPs for 24 h per generation after attachment. The results showed that with the increasing generations of the exposure, SiNPs decreased the viability of spermatocyte cells, induced apoptosis and increased the level of reactive oxygen species in spermatocyte cells. Moreover, SiNPs increased the protein expression of GRP-78, p-PERK, IRE1α, ATF6 and Cleaved caspase-3 in spermatocyte cells, suggesting that SiNPs improved unfolded protein response (UPR) and apoptosis. The present results indicated that the long-term and low-dose exposure to SiNPs could induce apoptosis by triggering ROS-mediated UPR in spermatocyte cells.

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An ER–Golgi Tethering Factor SLOH4/MIP3 Is Involved in Long-term Heat Tolerance of Arabidopsis

Plant and Cell Physiology ◽

10.1093/pcp/pcaa157 ◽

2020 ◽

Author(s):

Kazuho Isono ◽

Ryo Tsukimoto ◽

Satoshi Iuchi ◽

Akihisa Shinozawa ◽

Izumi Yotsui ◽

...

Keyword(s):

Heat Stress ◽

Heat Tolerance ◽

Secretory Proteins ◽

Wild Type ◽

Additional Function ◽

Transcript Levels ◽

Unfolded Protein ◽

In The Wild ◽

Protein Response

Abstract Plants are often exposed not only to short-term (S-) heat stress but also to diurnal long-term (L-) heat stress over several consecutive days. To reveal the mechanisms underlying L-heat stress tolerance, we here used a forward genetic screening for sensitive to long-term heat (sloh) mutants and isolated sloh4. The mutant was hypersensitive to L- but not S-heat stress. The causal gene of sloh4 was identical to MIP3 encoding a member of the MAIGO2 (MAG2) tethering complex, which is composed of the MAG2, MIP1, MIP2, and MIP3 subunits and is localized at the endoplasmic reticulum (ER) membrane. Although sloh4/mip3 was hypersensitive to L-heat stress, the sensitivity of the mag2-3 and mip1–1 mutants was similar to that of the wild type. Under L-heat stress, the ER stress and the following unfolded protein response (UPR) were more pronounced in sloh4 than in the wild type. Transcript levels of bZIP60-regulated UPR genes were strongly increased in sloh4 under L-heat stress. Two processes known to be mediated by INOSITOL REQUIRING ENZYME1 (IRE1)—accumulation of the spliced bZIP60 transcript and a decrease in the transcript levels of PR4 and PRX34, encoding secretory proteins—were observed in sloh4 in response to L-heat stress. These findings suggest that misfolded proteins generated in sloh4 under L-heat stress may be recognized by IRE1 but not bZIP28, resulting in initiation of the UPR via activated bZIP60. Therefore, it would be possible that only MIP3 in MAG2 complex has an additional function in L-heat tolerance, which is not related to the ER–Golgi vesicle tethering.

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RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

Cell Death and Disease ◽

10.1038/cddis.2014.523 ◽

2014 ◽

Vol 5 (12) ◽

pp. e1555-e1555 ◽

Cited By ~ 23

Author(s):

Y Estornes ◽

M A Aguileta ◽

C Dubuisson ◽

J De Keyser ◽

V Goossens ◽

...

Keyword(s):

Er Stress ◽

Molecular Mechanisms ◽

Death Receptor ◽

Caspase 8 ◽

Interacting Protein ◽

Life And Death ◽

Unfolded Protein ◽

Induced Apoptosis ◽

The Unfolded Protein Response ◽

Protein Response

Abstract Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)—a kinase at the crossroad between life and death downstream of various receptors—as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).

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Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

10.21203/rs.3.rs-24673/v1 ◽

2020 ◽

Author(s):

Guiqing Zhou ◽

Jianhui Liu ◽

Xiangyang Li ◽

Yujian Sang ◽

Yue Zhang ◽

...

Keyword(s):

Cytochrome C ◽

Silica Nanoparticles ◽

Caspase 3 ◽

Reproductive Toxicity ◽

Control Group ◽

Caspase 9 ◽

Protein Expressions ◽

Underlying Mechanisms

Abstract Background: Silica nanoparticles (SiNPs) are found in environmental particulate matter and are proven to have adverse effects on fertility. The relationship and underlying mechanisms between miRNAs and apoptosis induced by SiNPs during spermatogenesis is currently ambiguous. Experimental design: The present study was designed to investigate the role of miRNA-450b-3p in the reproductive toxicity caused by SiNPs. In vivo, 40 male mice were randomly divided into control and SiNPs groups, 20 per group. The mice in the SiNPs group were administrated 20 mg/kg SiNPs by tracheal perfusion once every 5 days, for 35 days, and the control group were given the equivalent of a normal luminal saline. In vitro, spermatocyte cells were divided into 0 and 5 μg/mL SiNPs groups, after passaged for 30 generations, the GC-2spd cells in 5 μg/mL SiNPs groups were transfected with miRNA-450b-3p and its mimic and inhibitor. Results: In vivo, the results showed that SiNPs damaged tissue structures of testis, decreased the quantity and quality of the sperm, reduced the expression of miR-450b-3p, and increased the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, and Caspase-3 in the testis. In vitro, SiNPs obviously repressed the viability and increased the LDH level and apoptosis rate, decreased the levels of the miR-450b-3p, significantly enhanced the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, Caspase-3; while the mimic of miR-450b-3p reversed the changes induced by SiNPs, but inhibitor further promoted the effects induced by SiNPs.Conclusion: The result suggested that SiNPs could induce the spermatocyte apoptosis by inhibiting the miR-450b-3p expression to target promoting the MTCH2 resulting in activating mitochondrial apoptotic signaling pathways in the spermatocyte cells.

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Tunicamycin Sensitizes Human Melanoma Cells to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis by Up-regulation of TRAIL-R2 via the Unfolded Protein Response

Cancer Research ◽

10.1158/0008-5472.can-07-0213 ◽

2007 ◽

Vol 67 (12) ◽

pp. 5880-5888 ◽

Cited By ~ 90

Author(s):

Chen Chen Jiang ◽

Li Hua Chen ◽

Susan Gillespie ◽

Kelly A. Kiejda ◽

Nizar Mhaidat ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Unfolded Protein Response ◽

Tumor Necrosis ◽

Melanoma Cells ◽

Human Melanoma ◽

Unfolded Protein ◽

Induced Apoptosis ◽

The Unfolded Protein Response ◽

Protein Response ◽

Necrosis Factor

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The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00449.2015 ◽

2016 ◽

Vol 311 (5) ◽

pp. L846-L854 ◽

Cited By ~ 15

Author(s):

Hang Nguyen ◽

Bruce D. Uhal

Keyword(s):

Epithelial Cells ◽

Er Stress ◽

Unfolded Protein Response ◽

Cathepsin D ◽

Lung Epithelial Cells ◽

Chemical Chaperone ◽

Unfolded Protein ◽

Induced Apoptosis ◽

The Unfolded Protein Response ◽

Protein Response

Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the proapoptotic cathepsin D and reducing antiapoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system. A549 cells were challenged with MG132 or SP-C BRICHOS domain mutant G100S to induce ER stress and activation of UPR pathways. The results showed that either MG132 or G100S SP-C mutation activated all three canonical pathways of the UPR (IRE1/XBP1, ATF6, and PERK/eIF2α), which led to a significant increase in cathepsin D or in TACE (an ACE-2 ectodomain shedding enzyme) and eventually caused AEC apoptosis. However, ER stress-induced AEC apoptosis could be prevented by chemical chaperone or by UPR blockers. It is also suggested that ATF6 and IRE1 pathways might play important role in regulation of angiotensin system. These data demonstrate that ER stress induces apoptosis in human AECs through mediation of UPR pathways, which in turn regulate the autocrine ANGII/ANG1-7 system. They also demonstrated that ER stress-induced AEC apoptosis can be blocked by inhibition of UPR signaling pathways.

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