The combined effect of acetylation and glycation on the chaperone and anti-apoptotic functions of human α-crystallin

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Nahomi, Rooban B.¹  Oya-Ito, Tomoko³  Nagaraj, Ram H.^1,2 

[1] Case Western Reserve Univ, Sch Med, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA

[3] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Kyoto, Japan

关键词: Acetylation;    alpha-Crystallin;    Chaperone;    Glycation;    Apoptosis;   

DOI  :  10.1016/j.bbadis.2012.08.015

来源: Elsevier

【 摘 要 】

N-epsilon-acetylation occurs on select lysine residues in alpha-crystallin of the human lens and alters its chaperone function. In this study, we investigated the effect of N-epsilon-acetylation on advanced glycation end product (AGE) formation and consequences of the combined N-epsilon-acetylation and AGE formation on the function of alpha-crystallin. Immunoprecipitation experiments revealed that N-epsilon-acetylation of lysine residues and AGE formation co-occurs in both alpha A- and alpha B-crystallin of the human lens. Prior acetylation of alpha A- and alpha B-aystallin with acetic anhydride (Ac2O) before glycation with methylglyoxal (MGO) resulted in significant inhibition of the synthesis of two AGEs, hydroimidazolone (HI) and argpyrimidine. Similarly, synthesis of ascorbate-derived AGEs, pentosidine and N-epsilon-carboxymethyl lysine (CML), was inhibited in both proteins by prior acetylation. In all cases, inhibition of AGE synthesis was positively related to the degree of acetylation. While prior acetylation further increased the chaperone activity of MGO-glycated alpha A-crystallin, it inhibited the loss of chaperone activity by ascorbate-glycation in both proteins. BioPORTER-mediated transfer of alpha A- and alpha B-crystallin into CHO cells resulted in significant protection against hyperthermia-induced apoptosis. This effect was enhanced in acetylated and MGO-modified alpha A- and alpha B-crystallin. Caspase-3 activity was reduced in alpha-crystallin transferred cells. Glycation of acetylated proteins with either MGO or ascorbate produced no significant change in the anti-apoptotic function. Collectively, these data demonstrate that lysine acetylation and AGE formation can occur concurrently in alpha-crystallin of human lens, and that lysine acetylation improves anti-apoptotic function of alpha-crystallin and prevents ascorbate-mediated loss of chaperone function. (c) 2012 Elsevier B.V. All rights reserved.

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