F-box only protein 9 is an E3 ubiquitin ligase of PPARγ

Lee, Kyeong Won; Kwak, Soo Heon; Koo, Young Do; Cho, Yun Kyung; Lee, Hak Mo; Jung, Hye Seung; Cho, Young Min; Park, Young Joo; Chung, Sung Soo; Park, Kyong Soo

doi:10.1038/emm.2016.31

Cited by 25 publications

(28 citation statements)

References 23 publications

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“…The genes mapped by these sites were reported to be closely associated with multiple metabolic diseases (Table 5). For instance, SQSTM1 and FBXO9 were related with diabetes mellitus [32, 33]. GRWD1 and ATP10A were involved with insulin resistance [34-36].…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution

Yao¹,

Mo²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metabolic diseases are leading health concerns in today’s global society. In traditional Chinese medicine (TCM), one body type studied is the phlegm-dampness constitution (PC), which predisposes individuals to complex metabolic disorders. Genomic studies have revealed the potential metabolic disorders and the molecular features of PC. The role of epigenetics in the regulation of PC, however, is unknown. Methods: We analyzed a genome-wide DNA methylation in 12 volunteers using Illumina Infinium Human Methylation450 BeadChip on peripheral blood mononuclear cells (PBMCs). Eight volunteers had PC and 4 had balanced constitutions. Results: Methylation data indicated a genome-scale hyper-methylation pattern in PC. We located 288 differentially methylated probes (DMPs). A total of 256 genes were mapped, and some of these were metabolic-related. SQSTM1, DLGAP2 and DAB1 indicated diabetes mellitus; HOXC4 and SMPD3, obesity; and GRWD1 and ATP10A, insulin resistance. According to Ingenuity Pathway Analysis (IPA), differentially methylated genes were abundant in multiple metabolic pathways. Conclusion: Our results suggest the potential risk for metabolic disorders in individuals with PC. We also explain the clinical characteristics of PC with DNA methylation features.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution

Yao¹,

Mo²,

Wang³

et al. 2018

Cell Physiol Biochem

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“…In parallel, the Shh/Smo/ERK axis decreased the PPAR␥ protein level. Furthermore, the E3 ubiquitin ligases, CUL4B, FBXO9, MuRF2, MuRF3, and Siah2 regulate PPAR␥ ubiquitination in adipocytes, thus decreasing adipogenesis and lipogenesis (40,(43)(44)(45)(46). Other E3 ligases, such as MKRN1 and MDM2, are also involved in PPAR␥ ubiquitination and proteasome-dependent degradation (47,48).…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signaling instigates high-fat diet–induced insulin resistance by targeting PPARγ stability

Yao

Liu

Xiao

et al. 2019

Journal of Biological Chemistry

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Obesity is a major risk for patients with chronic metabolic disorders including type 2 diabetes. Sonic hedgehog (Shh) is a morphogen that regulates the pancreas and adipose tissue formation during embryonic development. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear receptor superfamily and one of the most important regulators of insulin action. Here, we evaluated the role and mechanism of Shh signaling in obesity-associated insulin resistance and characterized its effect on PPAR␥. We showed that Shh expression was up-regulated in subcutaneous fat from obese mice. In differentiated 3T3-L1 and primary cultured adipocytes from rats, recombinant Shh protein and SAG (an agonist of Shh signaling) activated an extracellular signal-regulated kinase (ERK)-dependent noncanonical pathway and induced PPAR␥ phosphorylation at serine 112, which decreased PPAR␥ activity. Meanwhile, Shh signaling degraded PPAR␥ protein via binding of PPAR␥ to neural precursor cell-expressed developmentally down-regulated protein 4-1 (NEDD4-1). Furthermore, vismodegib, an inhibitor of Shh signaling, attenuated ERK phosphorylation induced by a high fat diet (HFD) and restored PPAR␥ protein level, thus ameliorating glucose intolerance and insulin resistance in obese mice. Our finding suggests that Shh in subcutaneous fat decreases PPAR␥ activity and stability via activation of an ERK-dependent noncanonical pathway, resulting in impaired insulin action. Inhibition of Shh may serve as a potential therapeutic approach to treat obesity-related diabetes.

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“…We generated a mutant form of Fbxo9 lacking the F-box motif (Fbxo9ΔF; Fig. 7A), which is able to bind to its substrates without inducing ubiquitination (22). As expected, expression of Neurog2 protein persisted in Sox10 + cells overexpressing Fbxo9ΔF in the DRG, whereas Neurog2 was barely detectable in the vector control (Fig.…”

Section: Overexpression Of Fbxo9 Mutant Stabilizes Neurog2 Protein Andmentioning

confidence: 74%

“…It has been shown that Fbxo9 is augmented in human coronary arterial smooth muscle cells under high glucose culture and in the vessels of streptozotocin-induced diabetic rat, leading to UPS-mediated BK-β 1 degradation. In addition, Fbxo9 was shown to be required for adipocyte differentiation through modulating the level of peroxisome proliferator-activated receptor gamma protein (21,22). Another study showed that, in response to growth factor deprivation, Fbxo9-mediated ubiquitination of telomere maintenance 2 (Tel2) and Tel2 interacting protein 1 (Tti1) inactivated mTORC1, but activated the PI(3)K/TORC2/ Akt pathway to promote survival in multiple myeloma (23).…”

Section: Significancementioning

confidence: 99%

Fbxo9 functions downstream of Sox10 to determine neuron-glial fate choice in the dorsal root ganglia through Neurog2 destabilization

Liu

Tai

Hong

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor Sox10 is a key regulator in the fate determination of a subpopulation of multipotent trunk neural crest (NC) progenitors toward glial cells instead of sensory neurons in the dorsal root ganglia (DRG). However, the mechanism by which Sox10 regulates glial cell fate commitment during lineage segregation remains poorly understood. In our study, we showed that the neurogenic determinant Neurogenin 2 (Neurog2) exhibited transient overlapping expression with Sox10 in avian trunk NC progenitors, which progressively underwent lineage segregation during migration toward the forming DRG. Gain- and loss-of-function studies revealed that the temporary expression of Neurog2 was due to Sox10 regulation of its protein stability. Transcriptional profiling identified Sox10-regulated F-box only protein (Fbxo9), which is an SCF (Skp1-Cul-F-box)-type ubiquitin ligase for Neurog2. Consistently, overexpression of Fbxo9 in NC progenitors down-regulated Neurog2 protein expression through ubiquitination and promoted the glial lineage at the expense of neuronal differentiation, whereas Fbxo9 knockdown resulted in the opposite phenomenon. Mechanistically, we found that Fbxo9 interacted with Neurog2 to promote its destabilization through the F-box motif. Finally, epistasis analysis further demonstrated that Fbxo9 and probably other F-box members mediated the role of Sox10 in destabilizing Neurog2 protein and directing the lineage of NC progenitors toward glial cells rather than sensory neurons. Altogether, these findings unravel a Sox10–Fbxo9 regulatory axis in promoting the glial fate of NC progenitors through Neurog2 destabilization.

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F-box only protein 9 is an E3 ubiquitin ligase of PPARγ

Cited by 25 publications

References 23 publications

Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution

Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution

Sonic hedgehog signaling instigates high-fat diet–induced insulin resistance by targeting PPARγ stability

Fbxo9 functions downstream of Sox10 to determine neuron-glial fate choice in the dorsal root ganglia through Neurog2 destabilization

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