Ginkgolic acid, a sumoylation inhibitor, promotes adipocyte commitment but suppresses adipocyte terminal differentiation of mouse bone marrow stromal cells

Liu, Huadie; Li, Jianshuang; Lu, Di; Li, Jie; Liu, Minmin; He, Yuanzheng; Williams, Bart O.; Li, Jia‐Da; Yang, Tao

doi:10.1038/s41598-018-20244-0

Cited by 21 publications

(25 citation statements)

References 45 publications

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“…Oxidative stress-induced aberrant Sumoylation-mediated signaling is known to cause disruption of genes/proteins responsible for maintaining cellular homeostasis and cytoprotection [ 13 , 14 , 17 ]. Thus, we next sought to determine whether GA would restore Sp1-DNA binding activity lost to adverse signaling induced by oxidative stress caused by H 2 O 2 and/or ultra violet (UV) B, as reported by our group and others [ 5 , 6 , 18 , 44 , 47 , 48 ]. mLECs were pretreated with DMSO as sham or GA for 4 h, and then exposed to different concentrations of H 2 O 2 and/or UVB radiation ( Figure 9 C).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, global protein Sumoylation analysis of LECs treated with GA showed a significant inhibition in the global Sumoylation status as shown in Figure 3 . It has been reported that cells treated with GA show a dramatic global reduction in Sumo conjugates [ 48 , 73 ]. The major goal of our study was to determine whether GA has the ability to restore Sumoylation-mediated dysregulation of Sp1 and repression of its target gene Prdx6 [ 13 , 20 , 40 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

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Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities

Chhunchha

Singh

et al. 2018

IJMS

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Sumoylation is a downstream effector of aging/oxidative stress; excess oxidative stress leads to dysregulation of a specificity protein1 (Sp1) and its target genes, such as Peroxiredoxin 6 (Prdx6), resulting in cellular damage. To cope with oxidative stress, cells rely on a signaling pathway involving redox-sensitive genes. Herein, we examined the therapeutic efficacy of the small molecule Ginkgolic acid (GA), a Sumoylation antagonist, to disrupt aberrant Sumoylation signaling in human and mouse lens epithelial cells (LECs) facing oxidative stress or aberrantly expressing Sumo1 (small ubiquitin-like modifier). We found that GA globally reduced aberrant Sumoylation of proteins. In contrast, Betulinic acid (BA), a Sumoylation agonist, augmented the process. GA increased Sp1 and Prdx6 expression by disrupting the Sumoylation signaling, while BA repressed the expression of both molecules. In vitro DNA binding, transactivation, Sumoylation and expression assays revealed that GA enhanced Sp1 binding to GC-boxes in the Prdx6 promoter and upregulated its transcription. Cell viability and intracellular redox status assays showed that LECs pretreated with GA gained resistance against oxidative stress-driven aberrant Sumoylation signaling. Overall, our study revealed an unprecedented role for GA in LECs and provided new mechanistic insights into the use of GA in rescuing LECs from aging/oxidative stress-evoked dysregulation of Sp1/Prdx6 protective molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities

Chhunchha

Singh

et al. 2018

IJMS

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“…The timing of fat loss in Ubc9 a-KO mice is consistent with a period of hypertrophic WAT expansion [24], impairments of which degrade adipocyte maturation and endocrine functions. Accordingly, inhibition of SUMOylation in differentiated cells [25] decreased adipocyte lipid storage and maturation (Pparg, C/ebpa, Fabp4). Collectively, these observations suggest Ubc9 has a distinct role in adult adipocyte function, maturation, and survival.…”

Section: Discussionmentioning

confidence: 99%

Ubc9deletion in adipocytes causes lipoatrophy in mice

Cox

Chernis

Kim

et al. 2020

Preprint

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Objective: White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2- conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown. Methods: To determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth. Results: To our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. Conclusions: Our results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

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“…On the contrary, streptonigrin (SN), a natural product isolated from Streptomyces flocculus , acts as an inhibitor of SENPs by disrupting SENP1-SUMO1 interaction, with higher inhibitory effect against SENP1 than other SENPs (Ambaye et al, 2018). Its inhibitory effect on SUMO-2/3 was also detected in different cell lines (Liu et al, 2018; Qiu et al, 2018). We first examined effects of GA on Trx2 processing.…”

Section: Resultsmentioning

confidence: 84%

A Unique SUMO-Interacting Motif of Trx2 Is Critical for Its Mitochondrial Presequence Processing and Anti-oxidant Activity

et al. 2019

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Objective Mitochondrial thioredoxin 2 (Trx2) is a vital mitochondrial redox protein that mediates normal protein thiol reduction and provides electrons to peroxiredoxin 3 (Prx3) to scavenge H 2 O 2 in mitochondria. It has been widely reported that Trx2 deletion in cells or mice generates massive reactive oxygen species (ROS) which have been implicated in many pathological processes. On the contrary, how ROS regulate Trx2 processing and activity remains to be elucidated. Approach and Results Here we show that excess ROS induce endothelial cell senescence concomitant with an attenuation of Trx2 processing in which Trx2 presequence [i.e., mitochondrial targeting signal peptide (MTS)] is cleaved to generate a mature form. Mutation analyses indicate that Trx2 processing is mediated by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP)-recognition sites within the MTS. Interestingly, a mutation at a SUMO- interacting motif (SIM), but not the catalytic sites within the mature Trx2 protein, completely blocks Trx2 processing with no effect on Trx2 mitochondrial targeting. Consistently, chemical inhibition of protein SUMOylation attenuates, while SUMOylation agonist promotes, Trx2 processing. Moreover, we identify the α–MPP subunit is a SUMOylated protein that potentially mediates Trx2-binding and cleavage. Furthermore, the unprocessed form of Trx2-SIM is unable to protect cells from both ROS generation and oxidative stress-induced cellular senescence. Conclusion Our study reveals that a unique SUMO-interacting motif of Trx2 is critical for its mitochondrial processing and subsequent anti-oxidant/antisenescence activities.

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Ginkgolic acid, a sumoylation inhibitor, promotes adipocyte commitment but suppresses adipocyte terminal differentiation of mouse bone marrow stromal cells

Cited by 21 publications

References 45 publications

Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities

Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities

Ubc9deletion in adipocytes causes lipoatrophy in mice

A Unique SUMO-Interacting Motif of Trx2 Is Critical for Its Mitochondrial Presequence Processing and Anti-oxidant Activity

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