Txnip balances metabolic and growth signaling via PTEN disulfide reduction

Hui, Simon T.; Andres, Allen M.; Miller, Amber K.; Spann, Nathanael J.; Potter, D. W.; Post, Noah; Chen, Amelia Z.; Sachithanantham, Sowbarnika; Jung, Dae Young; Kim, Jason K.; Davis, Roger J.

doi:10.1073/pnas.0800293105

Cited by 197 publications

(238 citation statements)

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“…Other groups have previously shown that TXNIP deficiency induces AKT activation via oxidative inactivation of PTEN in the soleus muscle and heart, and TXNIP is phosphorylated by AKT in response to insulin (Hui et al, 2008; Waldhart et al, 2017). To elucidate the correlation between TXNIP and AKT, we examined whether TXNIP interacts with AKT in cells.…”

Section: Resultsmentioning

confidence: 99%

“…To examine the effect of TXNIP or AKT on glucose uptake in vivo, we performed a glucose tolerance test (GTT) on fasted WT and KO mice (Hui et al, 2008). KO mice showed more significant glucose tolerance than WT mice from the beginning of the experiment, and glucose tolerance was significantly decreased by AKT inhibition in both WT and KO mice from 2 hr later (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we examined the induction of glucose uptake in KO MEF cells (Figure 1i) and KO mice (Figure 4a,b, 5a, and Supporting Information Figure S4D). Although previous reports have revealed the role of TXNIP in the regulatory mechanisms of glucose uptake and glucose metabolism in cancer and primary cells, the function of TXNIP in cellular senescence under glucose stress has not been reported (DeBalsi et al, 2014; Hui et al, 2008; Wu et al, 2013). High glucose is a well‐known inducer of cellular ROS and accelerates the senescence of cells (Mortuza et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…TXNIP was shown to suppress glucose uptake by regulating glucose transporter 1 (GLUT1) localization and expression (Wu et al, 2013) and peripheral glucose metabolism (Parikh et al, 2007), and its expression in the liver is required for maintaining normal fasting glycemia and glucose production (Chutkow, Patwari, Yoshioka, & Lee, 2008). TXNIP regulates glycolysis and cell growth by reductive reactivation of phosphatase and tensin homolog (PTEN), and TXNIP deficiency results in protein kinase B (AKT) activation in oxidative tissues (Hui et al, 2008). TXNIP expression is related to mitochondrial fuel switching under conditions of starvation, diabetes, and exercise in skeletal muscle (DeBalsi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we suggested that TXNIP is highly expressed and acts as an antioxidant protein to regulate cellular ROS by activating p53 activity or by inhibiting p38 mitogen‐activated protein kinase (MAPK) activity via direct interaction in hematopoietic stem cells (HSCs) (Jung & Choi, 2014; Jung et al, 2016, 2013 ). Importantly, TXNIP‐deficient mice are more glucose‐tolerant than wild‐type (WT) mice (Hui et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

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TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP‐/‐ MEF cells showed greater induced glucose uptake and ROS levels than wild‐type cells, and N‐acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP‐/‐ MEF cells. Interestingly, TXNIP‐/‐ MEF cells showed continuous activation of AKT during long‐term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP‐/‐ MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H2O2 treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging‐associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose‐derived metabolic stress.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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Structural basis for a novel interaction between TXNIP and Vav2

Zong

et al. 2016

FEBS Letters

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Edited by Lukas Alfons HuberThioredoxin-interacting protein (TXNIP) is a multifunctional protein involved in diverse cellular processes such as cell proliferation and apoptosis. TXNIP stability is controlled by the ubiquitin-proteasome pathway, and the E3 ubiquitin ligase Itch directly interacts with TXNIP via PPxY motifs of TXNIP. In a previously published study, we have shown that phosphorylation of the PPxY tyrosyl residue switches TXNIP selectivity between different binding partners. Here, we describe that tyrosine-phosphorylated PPxY motifs also bind to SH2 domains of Vav2 and Src with dissociation constants around 10 lM and that phosphorylation is indispensable for these interactions as well. The crystal structure of the complex between a phosphorylated PPxY motif, and the SH2 domain of Vav2 reveals a conserved recognition mechanism.

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Mitochondria: Sovereign of inflammation?

2011

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NLRP3 inflammasome-dependent inflammatory responses are triggered by a variety of signals of host danger, including infection, tissue damage and metabolic dysregulation. How these diverse activators cause inflammasome activation is poorly understood. Recent data suggest that the mitochondria integrate these distinct signals and relay this information to the NLRP3 inflammasome. Dysfunctional mitochondria generate ROS, which is required for inflammasome activation. On the contrary, the NLRP3 inflammasome is negatively regulated by autophagy, which is a catabolic process that removes damaged or otherwise dysfunctional organelles, including mitochondria. In addition to the processing and secretion of proinflammatory cytokines such as IL-1b, NLRP3 inflammasome activation also influences cellular metabolic pathways such as glycolysis and lipogenesis. Mapping the connections between mitochondria, metabolism and inflammation is of great interest, as malfunctioning of this network is associated with many chronic inflammatory diseases.Keywords: Immune regulation . Inflammation . Innate immunity See accompanying reviews by Bevan and Dinarello, also winners of the 2010 Novartis Immunology Prizes, and the Forum article describing the Prizes Detecting and repairing tissue damageA consequence of multicellularity is the necessity for coordinated repair mechanisms to respond to damage induced by environmental, intracellular and extracellular insults. Examples include pathogens, DNA damage and metabolic stress. To mount an appropriate repair response to these dangerous situations, the organism requires mechanisms that identify the source of the problem and engage suitable effectors. Tissue damage, cellular stress and infection are sensed by the innate immune system through pattern recognition receptors (PRRs), which, upon activation, initiate defense and repair programs [1,2]. If the cellular or tissue damage is extensive, these receptors trigger an acute inflammatory response. In the vast majority of cases, this response removes the injurious stimuli and repairs the damaged tissue within days of its initiation. In some situations, however, the source of tissue or cellular stress cannot be effectively resolved. Continued death of damaged cells leads to progressive destruction of the tissue, while the immune system initiates futile attempts to repair the damage. This simultaneous destruction and healing of tissue is characteristic of chronic inflammation, and is seen in a number of degenerative disease including arthritis, diabetes, inflammatory bowel diseases and many more (see accompanying review by Dinarello [3]).The NOD-like receptor family and the NLRP3 inflammasomeThe central role of the NOD-like receptor (NLR) family of cytoplasmic PRRs in the initiation of the inflammatory responses is becoming increasingly clear. NLRs typically have a tripartite architecture, consisting of a central and defining nucleotide binding and oligomerization (NACHT) domain, C-terminal leucine-rich repeats (LRRs) and an N-terminal effector domain ...

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Txnip balances metabolic and growth signaling via PTEN disulfide reduction

Cited by 197 publications

References 40 publications

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

Structural basis for a novel interaction between TXNIP and Vav2

Mitochondria: Sovereign of inflammation?

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