Eeyarestatin I

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Background

Eeyarestatin I (EerI [1]) is an inhibitor of endoplasmic reticulum-associated degradation (ERAD). It disturbs endoplasmic reticulum (ER) homeostasis and has anticancer activities resembling that of Bortezomib. ESI induced cell death in JEKO-1 cells with an IC50 of 4±1.2 µM [2]. ESI is also a potent inhibitor of protein translocation. The IC50 of ESI to ER translocation and N-glycosylation in vitro is ~70 µM [1].
ERAD pathway can eliminate misfolded ER proteins. Timely removing misfolded proteins from ER is involved in maintaining ER homeostasis [2]. N-Glycosylation is the most common and versatile protein modification, it occurs at the β-amide of the aspargine of the Asn-Xaa-Ser/Thr sequon [3]. ER mannosidase I could trigger the targeting of improperly folded glycoproteins to degradation [4].
In A9 cells, compared with Me2SO, treatment with EerI made polyubiquitinated MHC class I heavy chain (HC) accumulate in the cytosol. Compared with MG132, treatment with EerI resulted in very few deubiquitinated deglycosylated HC molecules, although a similar amount of accumulated polyubiquitinated HC [5]. In H1299 cells, treatment with EerI for 24 hrs significantly (p< 0.01) reduced cell proliferation (24.0%) as compared to the vehicle-treated control [6].
On the 2nd day and the 6th day after the subcutaneous injection of H1299 cells (8×106) complexed with Matrigel, athymic nude mice were treated with EerI (10 µM). EerI treatment significantly reduced tumor growth as compared to the DMSO vehicle control [6].

[1]. Benedict C. S. Cross, Craig McKibbin, Anna C. Callan, et al. Eeyarestatin I inhibits Sec61-mediated protein translocation at the endoplasmic reticulum. Journal of Cell Science, 2009, 122:4393-4400.
[2]. Qiuyan Wang, Bidhan A. Shinkre, Jin-gu Lee, et al. The ERAD Inhibitor Eeyarestatin I Is a Bifunctional Compound with a Membrane-Binding Domain and ap97/VCP Inhibitory Group. PLoS ONE, 2010, 5(11):e15479.
[3]. Shifra Ben-Dor, Nir Esterman, Eitan Rubin, et al. Biases and complex patterns in the residues flanking protein N-glycosylation sites. Glycobiology, 2004, 14(2):95-101.
[4]. Myriam Ermonval, Claudia Kitzmüller, Anne Marie Mir, et al. N-glycan structure of a short-lived variant of ribophorin I expressed in the MadIA214 glycosylation-defective cell line reveals the role of a mannosidase that is not ER mannosidase I in the process of glycoprotein degradation. Glycobiology, 2001, 11(7):565-576.
[5]. Qiuyan Wang, Lianyun Li and Yihong Ye. Inhibition of p97-dependent Protein Degradation by Eeyarestatin I. Journal of Biological Chemistry, 2008, 283(12):7445-7454.
[6]. Christopher W. Valle, Taehong Min, Manish Bodas, et al. Critical Role of VCP/p97 in the Pathogenesis and Progression of Non-Small Cell Lung Carcinoma. PLoS ONE, 2011, 6(12): e29073.