Death domain associated protein (Daxx), a multi-functional protein

Tang, Shuangyang; Wu, Yanping; Wu, Yimou

doi:10.1515/cmble-2015-0048

Cited by 16 publications

(16 citation statements)

References 12 publications

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“…Previous research has shown that the ox-LDLs is closely related to ASK1-induced apoptosis. 55 Another study demonstrated that phosphorylated ASK1 plays a key role in atherosclerosis development, 56 and that an ASK inhibitor (AGI-1067) exerts an antiinflammatory effect by inhibiting the dissociation of thioredoxin in vascular endothelial cells. 57 In addition, another study showed that thioredoxin-1 (Trx-1) could protect macrophages from ox-LDL-induced foam cell formation and apoptosis by interacting with ASK1.…”

Section: Discussionmentioning

confidence: 99%

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Hang

Peng

Xiang

et al. 2020

DDDT

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These authors contributed equally to this workObjective: This study was to investigate the mechanism of inflammatory pathology modification induced by ox-LDL in endothelial cells. Methodology: In this study, we firstly investigated the efflux of cholesterol of endothelial cells under the treatment of ox-LDL, and cell proliferation, ROS production, cell apoptosis was measured. Further, proteins of ASK1, NLRP3 inflammasomes and endoplasmic reticulum stress response were detected. Afterwards, ASK1 inhibitor (GS-4997) or endoplasmic reticulum stress (ERS) inhibitor (4-PBA) was used to measure the performance of endothelial cells. Results: In this study, endothelial cells were treated with ox-LDLs alone or in combination with a GS-4997 or 4-PBA. Results showed that ox-LDLs attenuated the efflux of cholesterol from endothelial cells in a dose-dependent manner. Ox-LDLs inhibited the proliferation of endothelial cells, and induced their apoptosis and production of reactive oxygen species (ROS). Additionally, ox-LDLs upregulated the levels of phosphorylated ASK1, ERS-related proteins (chop, p-PERK, GRP78, and p-IRE-1), and inflammation-associated proteins (NLRP3, IL-1β, and caspase 1) in endothelial cells. Moreover, we proved that GS-4997 could partly reverse ox-LDL-mediated cell proliferation, apoptosis, ROS production, and inflammation in endothelial cells, and increase cholesterol efflux. We also found that 4-PBA could attenuate the effects of ox-LDLs on endothelial cell cholesterol efflux, proliferation, apoptosis, ROS production, and inflammation. Conclusion: Our results suggest that cholesterol efflux from endothelial cells is reduced by ox-LDLs, and these reductions in cholesterol efflux are accompanied by increased NLRP3 inflammasome signaling, ASK1 and higher levels of endoplasmic reticulum stress. Our results suggest this axis as potential targets for treating atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

Hang

Peng

Xiang

et al. 2020

DDDT

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“…The present results verified the important role of DAXX in regulating high Pi-induced HUVECs apoptosis and may provide a novel opportunity to treat high Pi-induced endothelial cell apoptosis. DAXX can both promote and suppress apoptosis (Tang, Wan & Wu, 2015), and the specific mechanism of DAXX remains unclear. DAXX largely localizes to the nucleus of un-stimulated cells and exerts an anti-apoptotic effect in the nucleus (Tang, Wan & Wu, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…DAXX can both promote and suppress apoptosis (Tang, Wan & Wu, 2015), and the specific mechanism of DAXX remains unclear. DAXX largely localizes to the nucleus of un-stimulated cells and exerts an anti-apoptotic effect in the nucleus (Tang, Wan & Wu, 2015). Dionne et al (2013) demonstrated that DAXX has an anti-apoptotic effect on the HUVECs were overexpressed with DAXX in the presence or absence of U0126 (100 ng/mL), and then cell apoptosis was assessed using flow cytometric analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Death domain-associated protein (DAXX), a multifunctional nucleoprotein, plays an important roles in the regulation of cell apoptosis, gene transcription, tumorigenesis and anti-viral infection (Dyer et al, 2017;Li et al, 2013;Li et al, 2017;Tang, Wan & Wu, 2015). However, the exact roles and underlying mechanisms of DAXX in cell apoptosis are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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DAXX mediates high phosphate-induced endothelial cell apoptosis in vitro through activating ERK signaling

Wang

Qin

et al. 2020

PeerJ

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Backgroud and Purpose Hyperphosphatemia, which is a high inorganic phosphate (Pi) level in the serum, promotes endothelial cells dysfunction and is associated with cardiovascular diseases in patients with chronic kidney diseases (CKD). However, the underlying mechanism of high Pi-induced endothelia cell apoptosis remains unclear. Methods Human umbilical vein endothelial cells (HUVECs) were treated with normal Pi (1.0 mM) and high Pi (3.0 mM), and then cell apoptosis, abnormal gene expression and potential signaling pathway involvement in simulated hyperphosphatemia were examined using flow cytometry, quantitative PCR (qPCR) and western blot analysis. A two-step 5/6 nephrectomy was carried out to induce CKD and biochemical measurements were taken. Results The rat model of CKD revealed that hyperphosphatemia is correlated with an increased death-domain associated protein (DAXX) expression in endothelial cells. In vitro, high Pi increased the mRNA and protein expression level of DAXX in HUVECs, effects that were reversed by additional phosphonoformic acid treatment. Functionally, high Pi resulted in a significantly increased apoptosis in HUVECs, whereas DAXX knockdown markedly repressed high Pi-induced cell apoptosis, indicating that DAXX mediated high Pi-induced endothelial cell apoptosis. High Pi treatment and DAXX overexpression induced the activation of extracellular regulated protein kinases (ERKs), while DAXX knockdown inhibited high Pi-induced ERKs activation. Finally, we demonstrated that DAXX overexpression induced HUVECs apoptosis in the presence of normal Pi, whereas additional treatment with U0126 (a specific ERK inhibitor) reversed that effect. Conclusion Upregulated DAXX promoted high Pi-induced HUVECs apoptosis by activating ERK signaling and indicated that the DAXX/ERK signaling axis may be served as a potential target for CKD therapy.

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“…Daxx is a multifunctional, ubiquitously expressed and highly conserved protein through evolution. It has no enzymatic activity, but rather acts as a scaffold to bridge different proteins, thus regulating their function (reviewed in [ 41 , 42 , 43 ]). Although this multifunctional adapter is present in the cytoplasm, it is mainly expressed in the nucleus, where it localizes within promyelocytic leukemia protein (PML) nuclear bodies.…”

Section: Introductionmentioning

confidence: 99%

Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner

Maillet

Fernandez

Decourcelle

et al. 2020

Viruses

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Death domain-associated protein 6 (Daxx) is a multifunctional, ubiquitously expressed and highly conserved chaperone protein involved in numerous cellular processes, including apoptosis, transcriptional repression, and carcinogenesis. In 2015, we identified Daxx as an antiretroviral factor that interfered with HIV-1 replication by inhibiting the reverse transcription step. In the present study, we sought to unravel the molecular mechanism of Daxx-mediated restriction and, in particular, to identify the protein(s) that Daxx targets in order to achieve its antiviral activity. First, we show that the SUMO-interacting motif (SIM) located at the C-terminus of the protein is strictly required for Daxx to inhibit HIV-1 reverse transcription. By performing a quantitative proteomic screen combined with classical biochemical analyses, we found that Daxx associated with incoming HIV-1 cores through a SIM-dependent interaction with cyclophilin A (CypA) and capsid (CA). Daxx was found to reside within a multiprotein complex associated with viral capsids, also containing TNPO3, TRIM5α, and TRIM34. Given the well-known influence of these cellular factors on the stability of HIV-1 cores, we investigated the effect of Daxx on the cytoplasmic fate of incoming cores and found that Daxx prevented HIV-1 uncoating in a SIM-dependent manner. Altogether, our findings suggest that, by recruiting TNPO3, TRIM5α, and TRIM34 and possibly other proteins onto incoming HIV-1 cores through a SIM-dependent interaction with CA-bound CypA, Daxx increases their stability, thus preventing uncoating and reverse transcription. Our study uncovers a previously unknown function of Daxx in the early steps of HIV-1 infection and further illustrates how reverse transcription and uncoating are two tightly interdependent processes.

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Death domain associated protein (Daxx), a multi-functional protein

Cited by 16 publications

References 12 publications

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

DAXX mediates high phosphate-induced endothelial cell apoptosis in vitro through activating ERK signaling

Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner

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