The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice

Zhong, Linlin; Ding, Yun; Bandyopadhyay, Gautam; Waaler, Jo; Börgeson, Emma; Smith, Susan; Zhang, Mingchen; Phillips, Susan A.; Mahooti, Sepi; Mahata, Sushil K.; Shao, Jianhua; Krauß, Stefan; Chi, Nai‐Wen

doi:10.1007/s00125-015-3815-1

Cited by 34 publications

(39 citation statements)

References 44 publications

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“…Therefore, we considered that a deubiquitylating enzyme family member may act as the TUG protease. Among these enzymes, Usp25 (ubiquitin C-terminal hydrolase 25) was of particular interest because it was identified in a screen for proteins that bind tankyrase, an IRAP partner that regulates GLUT4 trafficking (17)(18)(19)(20)(21). In addition, Usp25 is present in distinct splice variants, including a muscle isoform that might account, at least in part, for the celltype specificity of TUG cleavage in myocytes and adipocytes (22,23).…”

Section: Resultsmentioning

confidence: 99%

“…All Usp25 isoforms bind tankyrase in vitro through the RXXPDG-like motif present at the Usp25 C terminus (17). Yet, the function of tankyrase in GLUT4 regulation is not well-understood and cannot be due solely to scaffolding of IRAP and Usp25m in proximity, because data imply that the poly(ADP-ribosylation) activity of tankyrase is involved (18,19,63). In skeletal muscle, Usp25m interacts with sarcomeric proteins (24).…”

Section: Usp25m Regulates Insulin Action In Adipocytesmentioning

confidence: 99%

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Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes

Habtemichael

Don

Alcázar-Román

et al. 2018

Journal of Biological Chemistry

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Insulin stimulates the exocytic translocation of specialized vesicles in adipocytes, which inserts GLUT4 glucose transporters into the plasma membrane to enhance glucose uptake. Previous results support a model in which TUG (ether containing a BX domain forLUT4) proteins trap these GLUT4 storage vesicles at the Golgi matrix and in which insulin triggers endoproteolytic cleavage of TUG to translocate GLUT4. Here, we identify the muscle splice form of Usp25 (Usp25m) as a protease required for insulin-stimulated TUG cleavage and GLUT4 translocation in adipocytes. Usp25m is expressed in adipocytes, binds TUG and GLUT4, dissociates from TUG-bound vesicles after insulin addition, and colocalizes with TUG and insulin-responsive cargoes in unstimulated cells. Previous results show that TUG proteolysis generates the ubiquitin-like protein, TUGUL (for biquitin-ike). We now show that TUGUL modifies the kinesin motor protein, KIF5B, and that TUG proteolysis is required to load GLUT4 onto these motors. Insulin stimulates TUG proteolytic processing independently of phosphatidylinositol 3-kinase. In nonadipocytes, TUG cleavage can be reconstituted by transfection of Usp25m, but not the related Usp25a isoform, together with other proteins present on GLUT4 vesicles. In rodents with diet-induced insulin resistance, TUG proteolysis and Usp25m protein abundance are reduced in adipose tissue. These effects occur soon after dietary manipulation, prior to the attenuation of insulin signaling to Akt. Together with previous data, these results support a model whereby insulin acts through Usp25m to mediate TUG cleavage, which liberates GLUT4 storage vesicles from the Golgi matrix and activates their microtubule-based movement to the plasma membrane. This TUG proteolytic pathway for insulin action is independent of Akt and is impaired by nutritional excess.

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Section: Resultsmentioning

confidence: 99%

Section: Usp25m Regulates Insulin Action In Adipocytesmentioning

confidence: 99%

Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes

Habtemichael

Don

Alcázar-Román

et al. 2018

Journal of Biological Chemistry

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“…Tankyrase-1 (TNKS1/PARP-5a/ARTD5) and the closely related homolog Tankyrase-2 (TNKS2/PARP-5b/ARTD6) are PARP enzymes that produce poly(ADP-ribose) to regulate multiple distinct cellular processes (Haikarainen et al, 2014; Hsiao and Smith, 2008), including telomere maintenance (Smith et al, 1998), mitosis (Chang et al, 2005, 2009; Dynek and Smith, 2004), glucose metabolism (Chi and Lodish, 2000; Yeh et al, 2009; Zhong et al, 2016), DNA strand break repair (Nagy et al, 2016), and Wnt signaling (Huang et al, 2009). TNKS1/2 modification of target proteins with poly(ADP-ribose) frequently marks them for processing by the ubiquitin ligase/proteosomal degradation system (reviewed in Haikarainen et al, 2014), thus allowing TNKS1/2 to regulate the levels of key components in signaling complexes.…”

Section: Introductionmentioning

confidence: 99%

Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling

et al. 2016

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SUMMARY Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that regulates multiple cellular processes creating a poly(ADP-ribose) posttranslational modification that can lead to target protein turnover. TNKS1 thereby controls protein levels of key components of signaling pathways, including Axin1, the limiting component of the destruction complex in canonical Wnt signaling that degrades β-catenin to prevent its coactivator function in gene expression. There are limited molecular level insights into TNKS1 regulation in cell signaling pathways. TNKS1 has a sterile alpha motif (SAM) domain that is known to mediate polymerization, but the functional requirement for SAM polymerization has not been assessed. We have determined the crystal structure of wild-type human TNKS1 SAM domain and used structure-based mutagenesis to disrupt polymer formation and assess the consequences on TNKS1 regulation of β-catenin dependent transcription. Our data indicate the SAM polymer is critical for TNKS1 catalytic activity and allows TNKS1 to efficiently access cytoplasmic signaling complexes.

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“…The Axin2 mutation likely exposes a physiological role of tankyrase in Wnt/β‐catenin signalling that may have been masked in the Tnks/Tnks2 double‐knockout mice, although alternative functions of the Axin N‐terminus cannot be excluded. A study otherwise focussing on the role of tankyrase in glucose metabolism corroborates the tankyrase‐Axin‐β‐catenin link in vivo : adipocyte‐specific loss of the Tnks catalytic domain stabilizes Axin1 and reduces the levels of active β‐catenin in adipose tissue (Zhong et al ., ).…”

Section: Tankyrase Mouse Modelsmentioning

confidence: 97%

“…Whether the observed toxicity is reversible has not been explored. Conversely, in a study investigating the role of tankyrase in glucose metabolism, the long‐term (6 months) treatment of mice with G007‐LK at a lower dose delivered orally, as opposed to intraperitoneally, did not result in detectable toxicity despite the observed stabilization of Axin1 and reduction in active β‐catenin levels (Zhong et al, ). As the expression of the Wnt pathway antagonist Dickkopf‐related protein 1 (Dkk1) in the gut epithelium gives rise to similar toxicity as highly dosed G007‐LK (Pinto et al, ; Kuhnert et al, ; Lau et al, ), it is likely that TNKSi toxicity is an on‐target, Wnt/β‐catenin pathway‐specific effect.…”

Section: Functional and Preclinical Studies Of Tankyrase Inhibitors Imentioning

confidence: 99%

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

Mariotti

Pollock

Guettler

2017

British J Pharmacology

112

120

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The Wnt/β‐catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration‐limited pathway components and a wide range of post‐translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP‐ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β‐catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the β‐catenin destruction complex, and targets it for degradation, thereby fine‐tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt‐dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/β‐catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re‐tune Wnt/β‐catenin signalling in colorectal cancer cells.Linked ArticlesThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

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The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice

Abstract: Systemic glucose homeostasis is regulated by the PARsylation activity of TNKS in adipocytes. This regulation is mediated in part by adipocyte-secreted factors that modulate hepatic glucose production. Pharmacological TNKS inhibition could potentially be used to improve glucose tolerance.

Cited by 34 publications

References 44 publications

Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes

Usp25m protease regulates ubiquitin-like processing of TUG proteins to control GLUT4 glucose transporter translocation in adipocytes

Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

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