scholarly journals Hexokinases inhibit death receptor–dependent apoptosis on the mitochondria

2021 ◽  
Vol 118 (33) ◽  
pp. e2021175118
Author(s):  
Joachim Lauterwasser ◽  
Franziska Fimm-Todt ◽  
Aline Oelgeklaus ◽  
Annabell Schreiner ◽  
Kathrin Funk ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Specific Resistance ◽  
Resistance Mechanism ◽  
Death Receptor ◽  
Protective Mechanism ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Death Receptor Signaling ◽  
Glucose Phosphorylation ◽  
Induced Apoptosis

Death receptor–mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor–induced apoptosis on the mitochondria.

scholarly journals Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

2010 ◽  
Vol 188 (6) ◽  
pp. 851-862 ◽  
Author(s):  
Bernhard Gillissen ◽  
Jana Wendt ◽  
Antje Richter ◽  
Anja Richter ◽  
Annika Müer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Death Receptor ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

Tumor necrosis factor (α)–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in the majority of tumor cells. Thus, TRAIL-induced cell death entirely depends on the proapoptotic Bcl-2 family member Bax, which is often lost as a result of epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against TRAIL-induced apoptosis. Despite expression of Bak, Bax-deficient cells are resistant to TRAIL-induced apoptosis. In this study, we show that the Bax dependency of TRAIL-induced apoptosis is determined by Mcl-1 but not Bcl-xL. Both are antiapoptotic Bcl-2 family proteins that keep Bak in check. Nevertheless, knockdown of Mcl-1 but not Bcl-xL overcame resistance to TRAIL, CD95/FasL and tumor necrosis factor (α) death receptor ligation in Bax-deficient cells, and enabled TRAIL to activate Bak, indicating that Mcl-1 rather than Bcl-xL is a major target for sensitization of Bax-deficient tumors for death receptor–induced apoptosis via the Bak pathway.

scholarly journals Human UDP-galactose 4′-epimerase (GALE) is required for cell-surface glycome structure and function

2019 ◽  
Vol 295 (5) ◽  
pp. 1225-1239
Author(s):  
Alex Broussard ◽  
Alyssa Florwick ◽  
Chelsea Desbiens ◽  
Nicole Nischan ◽  
Corrina Robertson ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Antigen ◽  
Mammalian Cells ◽  
Death Receptor ◽  
Cell Physiology ◽  
Total Sialic Acid ◽  
Death Receptor Signaling ◽  
Induced Apoptosis ◽  
And Function

Glycan biosynthesis relies on nucleotide sugars (NSs), abundant metabolites that serve as monosaccharide donors for glycosyltransferases. In vivo, signal-dependent fluctuations in NS levels are required to maintain normal cell physiology and are dysregulated in disease. However, how mammalian cells regulate NS levels and pathway flux remains largely uncharacterized. To address this knowledge gap, here we examined UDP-galactose 4′-epimerase (GALE), which interconverts two pairs of essential NSs. Using immunoblotting, flow cytometry, and LC-MS–based glycolipid and glycan profiling, we found that CRISPR/Cas9-mediated GALE deletion in human cells triggers major imbalances in NSs and dramatic changes in glycolipids and glycoproteins, including a subset of integrins and the cell-surface death receptor FS-7-associated surface antigen. In particular, we observed substantial decreases in total sialic acid, galactose, and GalNAc levels in glycans. These changes also directly impacted cell signaling, as GALE−/− cells exhibited FS-7-associated surface antigen ligand-induced apoptosis. Our results reveal a role of GALE-mediated NS regulation in death receptor signaling and may have implications for the molecular etiology of illnesses characterized by NS imbalances, including galactosemia and metabolic syndrome.

scholarly journals The human UDP-galactose 4’-epimerase (GALE) is required for cell surface glycome structure and function

2019 ◽  
Author(s):  
Alex Broussard ◽  
Alyssa Florwick ◽  
Chelsea Desbiens ◽  
Nicole Nischan ◽  
Corrina Robertson ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Fas Ligand ◽  
Death Receptor ◽  
Cell Physiology ◽  
Uridine Diphosphate ◽  
Death Receptor Signaling ◽  
Nucleotide Sugars ◽  
Induced Apoptosis ◽  
And Function

ABSTRACTGlycan biosynthesis relies on nucleotide-sugars (NS), abundant metabolites that serve as monosaccharide donors for glycosyltransferases. In vivo, signal-dependent fluctuations in NS levels are required to maintain normal cell physiology and are dysregulated in disease, but how mammalian cells regulate NS levels and pathway flux remains largely uncharacterized. To address this knowledge gap, we examined uridine diphosphate (UDP)-galactose 4’-epimerase (GALE), which interconverts two pairs of essential NSs. GALE deletion in human cells triggered major imbalances in its substrate NSs and consequent dramatic changes in glycolipids and glycoproteins, including a subset of integrins and the Fas death receptor. NS dysregulation also directly impacted cell signaling, as GALE−/− cells exhibit Fas hypoglycosylation and hypersensitivity to Fas ligand-induced apoptosis. Our results reveal a new role for GALE-mediated NS regulation in supporting death receptor signaling and may have implications for the molecular etiology of illnesses characterized by NS imbalances, including galactosemia and metabolic syndrome.

scholarly journals Glutathione peroxidase-1 regulates ASK1-dependent apoptosis via interaction with TRAF2 in RIPK3-negative cancer cells

2021 ◽  
Author(s):  
Sunmi Lee ◽  
Eun-Kyung Lee ◽  
Dong Hoon Kang ◽  
Jiyoung Lee ◽  
Soo Hyun Hong ◽  
...  
Keyword(s):  
Glutathione Peroxidase ◽  
Cancer Cells ◽  
Mammalian Cells ◽  
Apoptosis Pathway ◽  
Glutathione Peroxidase 1 ◽  
Peroxidase Enzyme ◽  
Thioredoxin 1 ◽  
Sequential Activation ◽  
Induced Apoptosis

AbstractGlutathione peroxidase (GPx) is a selenocysteine-containing peroxidase enzyme that defends mammalian cells against oxidative stress, but the role of GPx signaling is poorly characterized. Here, we show that GPx type 1 (GPx1) plays a key regulatory role in the apoptosis signaling pathway. The absence of GPx1 augmented TNF-α-induced apoptosis in various RIPK3-negative cancer cells by markedly elevating the level of cytosolic H2O2, which is derived from mitochondria. At the molecular level, the absence of GPx1 led to the strengthened sequential activation of sustained JNK and caspase-8 expression. Two signaling mechanisms are involved in the GPx1-dependent regulation of the apoptosis pathway: (1) GPx1 regulates the level of cytosolic H2O2 that oxidizes the redox protein thioredoxin 1, blocking ASK1 activation, and (2) GPx1 interacts with TRAF2 and interferes with the formation of the active ASK1 complex. Inducible knockdown of GPx1 expression impaired the tumorigenic growth of MDA-MB-231 cells (>70% reduction, P = 0.0034) implanted in mice by promoting apoptosis in vivo. Overall, this study reveals the apoptosis-related signaling function of a GPx family enzyme highly conserved in aerobic organisms.

scholarly journals Daxx Silencing Sensitizes Cells to Multiple Apoptotic Pathways

2003 ◽  
Vol 23 (20) ◽  
pp. 7108-7121 ◽  
Author(s):  
Liuh-Yow Chen ◽  
J. Don Chen
Keyword(s):  
Gene Expression ◽  
Transcriptional Repression ◽  
Mammalian Cells ◽  
Death Receptor ◽  
Kinase Activation ◽  
Transient Overexpression ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Caspase Gene ◽  
Interfering Rna

ABSTRACT Daxx is a nuclear protein involved in apoptosis and transcriptional repression, and it interacts with the death receptor Fas, promyelocytic leukemia protein (PML), and several transcriptional repressors. The function of Daxx in apoptosis is controversial because opposite results were obtained in transient overexpression and genetic knockout studies. Furthermore, the roles of PML and transcriptional repression in Daxx-regulated apoptosis are currently unknown. In this study, we investigated the role of Daxx in Fas- and stress-induced apoptosis by small interfering RNA-mediated Daxx silencing in mammalian cells. Daxx silencing had no apparent cytotoxic effects on mammalian cells within 72 h. Intriguingly, Daxx silencing strongly sensitized cells to Fas- and stress-induced apoptosis, which was accompanied by caspase activation, cytochrome c release, and Jun N-terminal kinase activation. Consistently, endogenous Daxx was degraded rapidly upon induction of apoptosis by stress or anti-Fas antibody. Finally, PML silencing had no effect on Daxx silencing-mediated apoptotic events, while caspase gene expression was upregulated in the absence of Daxx. These data strongly suggest that Daxx may inhibit Fas and stress-mediated apoptosis by suppressing proapoptotic gene expression outside of PML domains.

scholarly journals Lycium barbarumPolysaccharides Protect Rat Corneal Epithelial Cells against Ultraviolet B-Induced Apoptosis by Attenuating the Mitochondrial Pathway and Inhibiting JNK Phosphorylation

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Shaobo Du ◽  
Biao Han ◽  
Kang Li ◽  
Xuan Zhang ◽  
Xueli Sha ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Underlying Mechanism ◽  
Mitochondrial Pathway ◽  
Ultraviolet B ◽  
Lycium Barbarum ◽  
Apoptosis Pathway ◽  
Corneal Epithelial ◽  
Mitochondrial Apoptosis Pathway ◽  
Induced Apoptosis

Lycium barbarumpolysaccharides (LBPs) have been shown to play a key role in protecting the eyes by reducing the apoptosis induced by certain types of damage. However, it is not known whether LBPs can protect damaged corneal cells from apoptosis. Moreover, no reports have focused on the role of LBPs in guarding against ultraviolet B- (UVB-) induced apoptosis. The present study aimed to investigate the protective effect and underlying mechanism of LBPs against UVB-induced apoptosis in rat corneal epithelial (RCE) cells. The results showed that LBPs significantly prevented the loss of cell viability and inhibited cell apoptosis induced by UVB in RCE cells. LBPs also inhibited UVB-induced loss of mitochondrial membrane potential, downregulation ofBcl-2, and upregulation ofBaxand caspase-3. Finally, LBPs attenuated the phosphorylation of c-Jun NH2-terminal kinase (JNK) triggered by UVB. In summary, LBPs protect RCE cells against UVB-induced damage and apoptosis, and the underlying mechanism involves the attenuation of the mitochondrial apoptosis pathway and the inhibition of JNK phosphorylation.

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