Pleiotropic properties of ASK1

Sakauchi, Chihiro; Wakatsuki, Hiroaki; Ichijo, Hidenori; Hattori, Kazuki

doi:10.1016/j.bbagen.2016.09.028

Cited by 55 publications

(43 citation statements)

References 110 publications

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“…As a member of the mitogen-activated protein kinase (MAPK) family, ASK1 balances and integrates numerous endogenous and exogenous stimulations, making it possible for cells to appropriately respond to different stimuli. 54 However, the continuous stimulation of pathogenic factors can cause the persistent abnormal activation of ASK1, leading to tissue and cell damage during the course of disease. Previous research has shown that the ox-LDLs is closely related to ASK1-induced apoptosis.…”

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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“…ASK1 activity is regulated by diverse posttranslational modifications (PTMs), among which ubiquitination is a vital mechanism that precisely modulates ASK1 phosphorylation and activation. (18) E3 ubiquitin ligases play an important role in determining ASK1 ubiquitination types in a cell type-or stimulationdependent manner, thus modulating ASK1 activation or degradation. (19) Our previous study has shown that nonproteolytic polyubiquitination (including Lys63-, Lys29-, and Lys11-linked polyubiquitination) regulates ASK1 activation and contributes to the pathogenesis of NASH.…”

mentioning

confidence: 99%

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Wang

Wen

et al. 2019

Hepatology

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Activation of apoptosis signal‐regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte‐derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor–associated factor 6 (TRAF6) promotes lysine 6 (Lys6)‐linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet‐induced liver inflammation and fibrosis were substantially attenuated in Traf6+/– mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6‐linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N‐terminal dimerization of ASK1, resulting in the boosted activation of ASK1‐c‐Jun N‐terminal kinase 1/2 (JNK1/2)‐mitogen‐activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6‐linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6‐linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.

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“…Mouse ASK1 consists of 1380 amino acids with a kinase domain (KD) at the center flanked by N- and C-terminal regulatory regions (NT and CT, respectively) (Fig 2A). Accumulating evidence has shown that ASK1 activity is widely regulated by posttranslational modifications and protein-protein interactions at various regions in ASK1 [22,23]; hence, we sought to determine the interactive region between ASK1 and PKA. However, the results of immunoprecipitation analysis revealed that PKA interacts with all of the ASK1 fragments tested, including the CT, KD, and NT (Figs 2B and C).…”

Section: Resultsmentioning

confidence: 99%

“…Canonically, three-tiered cascades, MAPK kinase kinase (MAP3K)-MAPK kinase (MAP2K)-MAPK, are the central components of the MAPK pathway, and a tremendous variety of signaling is converged on two exclusive MAPKs, namely, p38s and JNKs [21]. The apoptosis signal-regulating kinase (ASK) family, which consists of ASK1, ASK2, and ASK3, is a member of MAP3K and shares similar amino acid sequences throughout the kinase domain but functions differently in many cases [22–24]. Additionally, ASKs can form heteromeric complexes and are mutually interactive in some cases [25–28].…”

Section: Introductionmentioning

confidence: 99%

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

Hattori

Wakatsuki

Sakauchi

et al. 2020

Preprint

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21Boosting energy expenditure by harnessing the activity of brown adipocytes is a promising 22 strategy for combatting the global epidemic of obesity. Many studies have revealed that the β3-adrenergic 23 receptor agonist is a potent activator of brown adipocytes, even in humans, and PKA and p38 MAPK have 24 been demonstrated for regulating the transcription of a wide range of critical genes such as Ucp1. We 25 previously revealed that the PKA-ASK1-p38 axis is activated in immature brown adipocytes and 26 contributes to functional maturation. However, the downstream mechanisms of PKA that initiate the p38 27 MAPK cascade are still mostly unknown in mature brown adipocytes. Here, we identified the ASK family 28 as a crucial signaling molecule bridging PKA and MAPK in mature brown adipocytes. Mechanistically, the 29 phosphorylation of ASK1 at threonine 99 and serine 993 is critical in PKA-dependent ASK1 activation. 30Additionally, PKA also activates ASK2, which contributes to MAPK regulation. These lines of evidence 31 provide new details for tailoring a βAR-dependent brown adipocyte activation strategy. 32 and the approved dose exhibits only limited effects; hence, off-target effects of β3AR agonists and cross-57 activation of β1AR and β2AR should be considered. Clinically, constructing selective methods for activating 58 β3AR on brown and/or beige adipocytes is crucial, but it is of critical importance to understand the signaling 59 mechanisms induced by β3AR agonists in mature brown adipocytes to fully understand the potential side 60 effects of β3AR agonism. However, a limited number of studies have uncovered the involvement of several 61 kinases in β3AR signaling [16][17][18][19]; specifically, the downstream targets of PKA are not fully known. 62Among a wide variety of signaling pathways, the stress-responsive mitogen-activated protein 63 kinase (MAPK) pathway regulates multiple functions such as gene expression and cell death depending on 64 cell types [20,21]. Canonically, three-tiered cascades, MAPK kinase kinase (MAP3K)-MAPK kinase 65 (MAP2K)-MAPK, are the central components of the MAPK pathway, and a tremendous variety of 66 signaling is converged on two exclusive MAPKs, namely, p38s and JNKs [21]. The apoptosis signal- 67regulating kinase (ASK) family, which consists of ASK1, ASK2, and ASK3, is a member of MAP3K and 68 shares similar amino acid sequences throughout the kinase domain but functions differently in many cases 69 [22][23][24]. Additionally, ASKs can form heteromeric complexes and are mutually interactive in some cases 70 [25][26][27][28]. Although the key role of ASK1 is cell death regulation [29][30][31][32][33], we previously reported that ASK1 71 also functions as a differentiation regulator through gene induction in immature brown adipocytes and 72 contributes to functional maturation [9]. However, there have been no reports regarding the functions of 73 the ASK family in mature brown adipocytes. Importantly, cell signaling patterns are incredibly diverse and 74 depend on many parameters,...

show abstract

Pleiotropic properties of ASK1

Cited by 55 publications

References 110 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>

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

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