TAK1: A Molecular Link Between Liver Inflammation, Fibrosis, Steatosis, and Carcinogenesis

Gao, Wenkang; Zhu, Qingjing; Alasbahi, Afnan; Seki, Ekihiro; Yang, Ling

doi:10.3389/fcell.2021.734749

Cited by 16 publications

(7 citation statements)

References 115 publications

(164 reference statements)

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“…For example, we noted significantly increased phosphorylation of JNK target site Ser350 (Table S8), which suppresses signalling IRS2 function (Solinas et al, 2006). Moreover, we observed activating phosphorylation on AMPK1alpha (Thr183), which is a target of MAPK3K/TAK1 (Wang et al, 2021) (Table S8), and a simultaneous increase on the activating AMPK target site on TSC2 – which results in inhibition of mTOR signalling downstream of Insulin (Inoki et al, 2003).…”

Section: Resultsmentioning

confidence: 90%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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The shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability. 3 IntroductionNuclear shape, size and architecture define the biophysics of key cellular processes such as transcription, replication, mRNA export, and DNA damage repair 1-4 . But nuclei are malleable viscoelastic structures 5, 6 that are frequently being stretched, strained, and compressed both by extracellular forces 7 , and the internal cytoskeleton 8-12 . Mechanisms have evolved to maintain nuclear shape and genome organization when cells are exposed to these forces 13 .Indeed, dysregulation of nuclear shape is coincident with numerous diseases including: muscular dystrophies, heart disease, and aging disorders such as progeria [14][15][16][17][18] . Thus in many cells, maintaining nuclear shape is essential for homeostasis.But while clearly maintenance of nuclear shape, size, and genome organization is essential for cellular homeostasis, transcriptional programmes that alter cell fate can be engaged by altering nuclear morphology and architecture 1,5,[19][20][21][22] . For example, nuclei undergo extensive shape changes that drive differentiation during development 23 . One means by which alteration in nuclear shape affects transcription is by affecting the nuclear translocation dynamics of transcription factors such as YAP/TAZ and NF-κB 24, 25 . Thus while in some cell types nuclear shape and genome organization are robust to deformation, in other cell types the nucleus is highly deformable.The importance of maintaining nuclear shape for cell, tissue, and organism homeostasis is highlighted by the fact that changes in nuclear morphology and genome organization are associated with cancer 4, 26 . For example, nuclear rupture is frequently an oncogenic event 27,28 . Indeed, pathologists have used nuclear shape as a diagnostic for over a century 29 . Irregular nuclear shapes and sizes are hall...

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Section: Resultsmentioning

confidence: 90%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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“…TAK1 is a key molecule in the regulation of in ammation and cell death and plays a critical role in regulating cell survival, differentiation and apoptosis. TAK1 activates NF-κB, promotes transcription of downstream anti-apoptotic proteins and promotes cell growth and proliferation (23). At the same time, inhibition or deletion of TAK1 can initiate RIPK1-mediated apoptosis or RIPK1-RIPK3-mediated necroptosis, promoting programmed cell death in a variety of cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GSK3β activity alleviates acute liver failure via suppressing multiple programmed cell death

Zhang

Shi

Zhang

et al. 2023

Preprint

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Background Acute liver failure (ALF) is one of the most common life-threatening diseases in adults without previous liver disease, and the construction of animal models using D- galactosamine(D-Gal) in combination with lipopolysaccharide(LPS) has been widely used to study the mechanisms of ALF and for drug development. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine protein kinase that is widely distributed in the cells. Inhibition of its activity can inhibit cell death and promote autophagy through various pathways, thus providing a protective effect. In this study, we aimed to investigate the effect on ALF after inhibition of GSK3β and its potential mechanisms. Methods A mouse ALF model was constructed using LPS/D-Gal, while D-Gal/TNF-α stimulated L02 cells were used to construct an in vitro model. After TDZD-8 treatment TUNEL staining and flow techniques were used to detect the proportion of apoptosis in liver tissues and cells respectively, while western blotting and immunofluorescence assays were performed to detect the expression levels of apoptosis, pyroptosis and necroptosis-related proteins in tissues and cells. In addition, to explore the specific mechanism of hepatoprotective effect after GSK3β inhibition, western blotting was performed to detect the expression levels of TAK1, TRAF6 and HDAC3 after TRAF6 and HDAC3 inhibition alone. The co-localization of TRAF6 and HDAC3 in L02 cells was detected by immunofluorescence, while the interaction between TRAF6 and HDAC3 was detected by immunoprecipitation assay. Results In both in vivo and in vitro experiments, we observed the hepatoprotective effect of GSK3β inhibitor TDZD-8 in ALF model through in vivo and in vitro experiments and found that inhibition of GSK3β activity could significantly reduce the level of hepatocyte apoptosis, pyroptosis, necroptosis and improve liver dysfunction and tissue damage. Furthermore, we found that hepatocyte TAK1 and TRAF6 levels decreased and HDAC3 levels increased in ALF, whereas inhibition of GSK3β upregulated TAK1 and TRAF6 levels and decreased HDAC3 expression. Conclusion This study investigated the protective effect of GSK3β inhibitor TDZD-8 on ALF, and its action may involve the TRAF6/HDAC3/TAK1 pathway.

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“…Another genetically modified liver fibrosis mouse model is a mouse with hepatocyte deletion of the TGF-β–activated kinase 1, a mitogen-activated protein kinase kinase kinase activated by interleukin 1, TGF-β, and Toll-like receptor ligands. 90 Hepatocyte-specific TGF-β–activated kinase 1 -/- mice spontaneously develop pericellular and periportal liver fibrosis from 1 month of age, followed by HCC formation at 6 months of age. 91 …”

Section: In Vivo Models Of Experimental Liver Fibrosismentioning

confidence: 99%

In Vivo and In Vitro Models to Study Liver Fibrosis: Mechanisms and Limitations

Lee

Seki

2023

Cellular and Molecular Gastroenterology and Hepatology

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TAK1: A Molecular Link Between Liver Inflammation, Fibrosis, Steatosis, and Carcinogenesis

Cited by 16 publications

References 115 publications

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Inhibition of GSK3β activity alleviates acute liver failure via suppressing multiple programmed cell death

In Vivo and In Vitro Models to Study Liver Fibrosis: Mechanisms and Limitations

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