The deubiquitinase JOSD2 is a positive regulator of glucose metabolism

Krassikova, Lyudmila; Zhang, Boxi; Nagarajan, Divya; Queiroz, André Lima; Kacal, Merve; Samakidis, Evangelos; Vakifahmetoglu-Norberg, Helin; Norberg, Erik

doi:10.1038/s41418-020-00639-1

Cited by 21 publications

(15 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As a member of Machado–Joseph Disease family, JOSD2 is reported to cleave poly-ubiquitin chains in vitro , while its cellular function remains elusive 24 . Recently, Norberg's group 25 , 26 reported that JOSD2 deubiquitinates and stabilizes 3 important components (aldolase A, phosphofructokinase-1 and phosphoglycerate dehydrogenase) of glucose metabolic enzyme complex, leading to enhanced glycolytic rate and lung adenocarcinomas progression. While Zhou et al.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Qian

Yan

et al. 2021

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo . Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Qian

Yan

et al. 2021

Acta Pharmaceutica Sinica B

View full text Add to dashboard Cite

show abstract

“…Furthermore, calcium promotes the binding of aldolase to the cytoskeleton in skeletal muscle ( 188 ). Deubiquitination of glycolytic enzymes including ALDOA and GAPDH is mediated by joshepin-2 in cancer cells, which stabilizes these enzymes and promotes glycolysis ( 189 ). However, whether joshepin-2 is responsible for the deubiquitination of glycolytic enzymes during exercise remains unknown.…”

Section: Post-translational Modifications At the Intersection Of Exer...mentioning

confidence: 99%

Post-translational Modifications: The Signals at the Intersection of Exercise, Glucose Uptake, and Insulin Sensitivity

Stocks

Zierath

2021

Endocrine Reviews

View full text Add to dashboard Cite

Diabetes is a global epidemic, of which type 2 diabetes makes up the majority of cases. Nonetheless, for some individuals, type 2 diabetes is eminently preventable and treatable via lifestyle interventions. Glucose uptake into skeletal muscle increases during and in recovery from exercise, with exercise effective at controlling glucose homeostasis in individuals with type 2 diabetes. Furthermore, acute, and chronic exercise sensitizes skeletal muscle to insulin. A complex network of signals converge and interact to regulate glucose metabolism and insulin sensitivity in response to exercise. Numerous forms of post-translational modifications (e.g. phosphorylation, ubiquitination, acetylation, ribosylation and more) are regulated by exercise. Here we review the current state-of-the-art of the role of post-translational modifications in transducing exercise-induced signals to modulate glucose uptake and insulin sensitivity within skeletal muscle. Furthermore, we consider emerging evidence for non-canonical signaling in the control of glucose homeostasis and the potential for regulation by exercise. While exercise is clearly an effective intervention to reduce glycemia and improve insulin sensitivity, the insulin- and exercise-sensitive signaling networks orchestrating this biology are not fully clarified. Elucidation of the complex proteome-wide interactions between post-translational modifications and the associated functional implications will identify mechanisms by which exercise regulates glucose homeostasis and insulin sensitivity. In doing so, this knowledge should illuminate novel therapeutic targets to enhance insulin sensitivity for the clinical management of type 2 diabetes.

show abstract

“…Several DUBs were reported to be involved in aerobic glycolysis via regulating glycolytic enzymes. In non-small cell lung cancer (NSCLC), deubiquitinase Josephin Domain-containing protein 2 (JOSD2) was recently identified to display comprehensive effects on glucose catabolism, and thereby promoting cancer cell proliferation [ 29 ]. Mechanistically, JOSD2 stabilizes metabolic enzymes aldolase A (ALDOA) and phosphofructokinase-1 (PFK1) in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Mechanistically, JOSD2 stabilizes metabolic enzymes aldolase A (ALDOA) and phosphofructokinase-1 (PFK1) in vitro and in vivo. Furthermore, JOSD2 expression, but not a catalytically inactive mutant, deubiquitinates and stabilizes the enzyme complex, thereby enhancing their activities and the glycolytic rate [ 29 ]. In hepatocellular carcinoma (HCC) cells, depletion of CSN5 (also known as COP9 signalosome subunit 5, COPS5 ) caused a significant decrease in glucose uptake and the production of glycolytic intermediates.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, enhancement of the serine synthesis pathway (SSP) is a major metabolic reprogramming event that is important for oncogenic transformation in many cancers [ 62 – 65 ]. In NSCLC, JOSD2 was also identified as a positive regulator of SSP via deubiquitinating and stabilizing phosphoglycerate dehydrogenase (PHGDH), a key enzyme that drives the first committed step in de novo serine biosynthesis [ 29 ]. In colorectal cancer (CRC), USP7 was reported to promote serine deprivation resistance.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The emerging role of deubiquitylating enzymes as therapeutic targets in cancer metabolism

Zhang

et al. 2022

Cancer Cell Int

View full text Add to dashboard Cite

Cancer cells must rewire cellular metabolism to satisfy the unbridled proliferation, and metabolic reprogramming provides not only the advantage for cancer cell proliferation but also new targets for cancer treatment. However, the plasticity of the metabolic pathways makes them very difficult to target. Deubiquitylating enzymes (DUBs) are proteases that cleave ubiquitin from the substrate proteins and process ubiquitin precursors. While the molecular mechanisms are not fully understood, many DUBs have been shown to be involved in tumorigenesis and progression via controlling the dysregulated cancer metabolism, and consequently recognized as potential drug targets for cancer treatment. In this article, we summarized the significant progress in understanding the key roles of DUBs in cancer cell metabolic rewiring and the opportunities for the application of DUBs inhibitors in cancer treatment, intending to provide potential implications for both research purpose and clinical applications.

show abstract

The deubiquitinase JOSD2 is a positive regulator of glucose metabolism

Cited by 21 publications

References 53 publications

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression

Post-translational Modifications: The Signals at the Intersection of Exercise, Glucose Uptake, and Insulin Sensitivity

The emerging role of deubiquitylating enzymes as therapeutic targets in cancer metabolism

Contact Info

Product

Resources

About