The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation

Xu, Xinsong; Sarikas, Antonio; Dias‐Santagata, Dora; Dolios, Georgia; Lafontant, Pascal J.; Tsai, Shih-Tzer; Zhu, Wuqiang; Nakajima, Hidehiro; Nakajima, Hisako O.; Field, Loren J.; Wang, Rong; Pan, Zheng

doi:10.1016/j.molcel.2008.03.009

Cited by 185 publications

(215 citation statements)

References 41 publications

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“…Previous studies already linked the proteasome-mediated degradation of IRS1 to the inhibition of insulin action in response to hyperinsulinaemia [35,36] and inflammation [37]. In this context, multiple E3-ligases, including F-box only protein 40, CBLB, and F-box/WD repeat-containing protein 8, have been linked to IRS1 degradation in response to hyperinsulinaemia, inflammation and chronic exposure to insulin-like growth factor 1 [37][38][39][40][41]. Furthermore, increased expression of Fbxo32 and Murf1 associated with reduced activation of the PI3K/Akt pathway by insulin was described in skeletal muscle of db/db mice [42].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Wiza

Nascimento

et al. 2013

Diabetologia

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Aims/hypothesis The proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex 1 (mTORC1) and among the most prominent Akt substrates in skeletal muscle. Yet the cellular functions of PRAS40 are incompletely defined. This study assessed the function of PRAS40 in insulin action in primary human skeletal muscle cells (hSkMC). Methods Insulin action was examined in hSkMC following small interfering RNA-mediated silencing of PRAS40 (also known as AKT1S1) under normal conditions and following chemokine-induced insulin resistance. Results PRAS40 knockdown (PRAS40-KD) in hSkMC decreased insulin-mediated phosphorylation of Akt by 50% (p<0.05) as well as of the Akt substrates glycogen synthase kinase 3 (40%) and tuberous sclerosis complex 2 (32%) (both p<0.05). Furthermore, insulin-stimulated glucose uptake was reduced by 20% in PRAS40-KD myotubes (p<0.05). Exposing PRAS40-KD myotubes to chemokines caused no additional deterioration of insulin action. PRAS40-KD further reduced insulin-mediated phosphorylation of the mTORC1-regulated proteins p70S6 kinase (p70S6K) (47%), S6 (43%), and eukaryotic elongation 4E-binding protein 1 (100%), as well as protein levels of growth factor receptor bound protein 10 (35%) (all p<0.05). The inhibition of insulin action in PRAS40-KD myotubes was associated with a reduction in IRS1 protein levels (60%) (p<0.05), and was reversed by pharmacological proteasome inhibition. Accordingly, expression of the genes encoding E3-ligases Fbox protein 32 (also known as atrogin-1) and muscle RINGfinger protein-1 and activity of the proteasome was elevated in PRAS40-KD myotubes. Conclusions/interpretation Inhibition of insulin action in PRAS40-KD myotubes was found to associate with IRS1 degradation promoted by increased proteasome activity rather than hyperactivation of the p70S6K-negative-feedback loop. These findings identify PRAS40 as a modulator of insulin action.

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Section: Discussionmentioning

confidence: 99%

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Wiza

Nascimento

et al. 2013

Diabetologia

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“…Since Cul7 is the only other known cullin that binds F-box proteins ( Fig. 1), [34][35][36] and FBG1 bound Cul1 poorly, we tested whether FBG1 binds Cul7. As seen in Figure 2 co-expression of any FBG protein, especially FBG1 and FBG3, with Cul7 increases the steady-state level of Cul7.…”

Section: Fbg1 Interacts With Different Cullinmentioning

confidence: 99%

“…The FBW8 F-box motif, which is known to bind Cul1, contains a glutamic acid at the third position, but the Cul7 binding site is undefined. 35,36 In a second example, FBXO45 was shown to lack an amino acid critical for cullin binding: the third residue in the F-box PXE motif is replaced with an R. This abrogates cullin binding by the F box; and FBXO45 instead binds another RING to bind misfolded glycoproteins. At this point of the cell cycle, APC2 forms an E3 ligase complex with CDC20 and other proteins to degrade mitotic substrates.…”

Section: Scf Ubiquitin Ligase Complex (Pdb Code 1ldk) Is Shown For Rementioning

confidence: 99%

FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest

Wen¹,

Kim

Fuentes

et al. 2010

Cell Cycle

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“…Insulin-induced IRS1 degradation relies on proteasome-dependent pathway (8), while osmotic stress and oxidative stress enhance IRS1 degradation in a proteasome-independent process (9,10). Cullin 7 (CUL7) is a key component of the multisubunit cullin-RING E3 ubiquitin ligase complex that targets IRS1 for ubiquitin-dependent degradation while ubiquitin specific protease 7 can deubiquitinate IRS1, preventing it from proteasomal degradation (11). However, molecular mechanisms regulating stability of IRS1 in response to cellular stress have not been well understood.…”

mentioning

confidence: 99%

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Sun

Tan

Huang

et al. 2018

Journal of Biological Chemistry

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Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

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The CUL7 E3 Ubiquitin Ligase Targets Insulin Receptor Substrate 1 for Ubiquitin-Dependent Degradation

Cited by 185 publications

References 41 publications

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

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