Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14

Liu, Bin; Zhang, Zhijian; Hu, Yanyun; Lu, Yan; Li, Duanzhuo; Liu, Jie; Liao, Shengjie; Hu, Min; Wang, Yuxing; Zhang, Die; Chen, Yulu; Qian, Qilan; Lv, Xianfeng; Wu, Duojiao; Tan, Minjia; Hu, Cheng; Xiong, Xuelian; Li, Xiaoying

doi:10.1073/pnas.1907288116

Cited by 46 publications

(35 citation statements)

References 51 publications

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“…Most stress-related factors, especially ER stress-related factors, are involved in the induction of gluconeogenesis [ 29 , 30 , 31 ]. Similarly, GADD45β, as a stress sensor and a fasting marker, induced hepatic gluconeogenesis.…”

Section: Discussionmentioning

confidence: 99%

GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1

Kim

Lee

et al. 2021

Biomedicines

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Increased hepatic gluconeogenesis is one of the main contributors to the development of type 2 diabetes. Recently, it has been reported that growth arrest and DNA damage-inducible 45 beta (GADD45β) is induced under both fasting and high-fat diet (HFD) conditions that stimulate hepatic gluconeogenesis. Here, this study aimed to establish the molecular mechanisms underlying the novel role of GADD45β in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45β exhibited decreased hepatic gluconeogenic gene expression concomitant with reduced blood glucose levels under fasting and HFD conditions, but showed a more pronounced effect in GADD45β KD mice. Further, in primary hepatocytes, GADD45β KD reduced glucose output, whereas GADD45β overexpression increased it. Mechanistically, GADD45β did not affect Akt-mediated forkhead box protein O1 (FoxO1) phosphorylation and forskolin-induced cAMP response element-binding protein (CREB) phosphorylation. Rather it increased FoxO1 transcriptional activity via enhanced protein stability of FoxO1. Further, GADD45β colocalized and physically interacted with FoxO1. Additionally, GADD45β deficiency potentiated insulin-mediated suppression of hepatic gluconeogenic genes, and it were impeded by the restoration of GADD45β expression. Our finding demonstrates GADD45β as a novel and essential regulator of hepatic gluconeogenesis. It will provide a deeper understanding of the FoxO1-mediated gluconeogenesis.

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Section: Discussionmentioning

confidence: 99%

GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1

Kim

Lee

et al. 2021

Biomedicines

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“…The in vivo ubiquitination assay has been described previously 21 . Briefly, 293T cells were transfected with HA-RNASET2 with or without Flag-FBXO6 and His-ubiquitin for 36 h. Cell lysates were sonicated in IP buffer with protease inhibitor cocktail and phosphorylate inhibitor for 10 min on ice.…”

Section: Methodsmentioning

confidence: 99%

FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer

Zhao

et al. 2021

Cell Death Dis

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RNASET2 (Ribonuclease T2) functions as a tumor suppressor in preventing ovarian tumorigenesis. However, the mechanisms underlying the regulation of RNASET2 protein are completely unknown. Here we identified the F-box protein FBXO6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin E3 ligase for RNASET2. We found that the interaction between FBXO6 and RNASET2 induced RNASET2 instability through the ubiquitin-mediated proteasome degradation pathway. FBXO6 promoted K48-dependent ubiquitination of RNASET2 via its FBA domain. Through analysis of the TCGA dataset, we found that FBXO6 was significantly increased in ovarian cancer tissues and the high expression of FBXO6 was related to the poor overall survival (OS) of ovarian cancer patients at advanced stages. An inverse correlation between the protein levels of FBXO6 and RNASET2 was observed in clinic ovarian cancer samples. Depletion of FBXO6 promoted ovarian cancer cells proliferation, migration, and invasion, which could be partially reversed by RNASET2 silencing. Thus, our data revealed a novel FBXO6-RNASET2 axis, which might contribute to the development of ovarian cancer. We propose that inhibition of FBXO6 might represent an effective therapeutic strategy for ovarian cancer treatment.

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“…An uncontrolled insulin demand promotes an increase in disulfide bond formation for correct protein folding at ER, a condition that increases the ROS formation [ 220 ]. As a consequence, protein folding fails and ER functions are impaired [ 221 ]. Mitochondrial oxidative stress and ER stress create a vicious cycle that increases oxidative stress and affects further the functioning of these determinant organelle.…”

Section: Mitochondrial Oxidative Stress and Mito-inflammation In Imentioning

confidence: 99%

Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases

et al. 2021

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A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases.

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Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14

Cited by 46 publications

References 51 publications

GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1

GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1

FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer

Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases

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