The E3 Ligase TRAF6 Regulates Akt Ubiquitination and Activation

Yang, Wei; Wang, Jing; Chan, Chia‐Hsin; Lee, Szu Wei; Campos, Alejandro D.; Lamothe, Betty; Hur, Lana; Grabiner, Brian C.; Lin, Xin; Darnay, Bryant G.; Lin, Hui Kuan

doi:10.1126/science.1175065

Cited by 546 publications

(642 citation statements)

References 28 publications

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“…Ubiquitin can be covalently attached to the lysine residues of target proteins by E3 ubiquitin ligase (Sun, 2006) and itself can also be ubiquitinated at Lys48 or Lys63 to form poly-ubiquitin chains (Ravid and Hochstrasser, 2007;Yang et al, 2009). Target proteins labeled with Lys48 poly-ubiquitination chains usually are recognized and degraded by the proteasome system (Pickart, 2001).…”

Section: Introductionmentioning

confidence: 99%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the e-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuininduced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.

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Section: Introductionmentioning

confidence: 99%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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“…57 Finally, AKT undergoes TRAF6-catalyzed K63-type ubiquitination at the PH domain upon exposure to growth factor, which promotes AKT membrane adherence, phosphorylation and activation without influencing its phosphatidylinositol (3,4,5)-trisphosphate lipidbinding capability. 58 Recent data showed that the activity of ULK1 is also regulated by ubiquitination. In cells undergoing autophagy, AMBRA1, a binding partner for both Beclin-1 and ULK1, in complex with TRAF6 supports K63-linked polyubiquitination and consequent self-association, stabilization and activation of ULK1.…”

Section: Involvement Of the Ubiquitin System In Antimicrobial Autophagymentioning

confidence: 99%

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

Chai

Liu

2016

Cell Mol Immunol

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The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.

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“…Akt activation is initiated by membrane recruitment, mainly through its PH domain-mediated phospho-lipid binding, 2 or in part through K63-linkage ubiquitination. 3 Membrane attachment subsequently induces a structural change to facilitate the phosphorylation of two critical residues: T308 in the Akt1 catalytic domain by PDK1 and S473 in the C-terminal hydrophobic motif by mTORC2 (also termed PDK2) for full Akt activation. Subsequently, activated Akt exerts its physiological functions by phosphorylating a wide spectrum of substrates.…”

mentioning

confidence: 99%