O-GlcNAcylation of light chain serine 12 mediates rituximab production doubled by thiamet G

Kim Hye-Yeon; Park Minseong; Kang Choeun; Heo Woon; Yoon Sei Mee; Lee Jinu; Kim Joo Young

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O-GlcNAcylation of light chain serine 12 mediates rituximab production doubled by thiamet G

机译：轻链丝氨酸12的o-glcnacylation介于紫外线G的介质产生的Rituximab生产

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O-Glycosylation occurs in recombinant proteins produced by CHO cells, but this phenomenon has not been studied extensively. Here, we report that rituximab is an O-linked N-acetyl-glucosaminylated (O-GlcNAcylated) protein and the production of rituximab is increased by thiamet G, an inhibitor of O-GlcNAcase. The production of rituximab doubled with OGA inhibition and decreased with O-GlcNAc transferase inhibition. O-GlcNAc-specific antibody and metabolic labelling with azidO-GlcNAc confirmed the increased O-GlcNAcylation with thiamet G. Protein mass analysis revealed that serine 7, 12, and 14 of the rituximab light chain were O-GlcNAcylated. S12A mutation of the light chain decreased rituximab stability and failed to increase the production with thiamet G without any significant changes of mRNA level. Cytotoxicity and thermal stability assays confirmed that there were no differences in the biological and physical properties of rituximab produced by thiamet G treatment. Therefore, thiamet G treatment improves the production of rituximab without significantly altering its function.

机译：O-糖基化发生在CHO细胞产生的重组蛋白中，但这种现象尚未被广泛研究。在此，我们报告利妥昔单抗是O-连接的N-乙酰基 - 吡糖胺蛋白化（O-Glcnacylated）蛋白，并且Rituximab的产生通过噻肟G，其抑制剂O-Glcnac酶的抑制剂。利妥昔单抗的产量加倍oga抑制并随o-glcnac转移酶抑制而降低。 o-glcnac特异性抗体和使用Azido-glcnac的代谢标记证实了含有G.蛋白质批量分析的o-glcnacylation的增加，显示丝氨酸7,12和14的Rituximab轻链是O-glcnaCate。轻链的S12A突变降低了利妥昔单抗稳定性，并且未能增加疗法G的产生，而没有MRNA水平的任何显着变化。细胞毒性和热稳定性测定证实，通过ThiaMet G处理产生的Rituximab的生物和物理性质没有差异。因此，疗法G治疗改善了利妥昔单抗的生产，而不会显着改变其功能。

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来源
《Bioprocess and Biosystems Engineering》 |2020年第5期|863-875|共13页
作者
Kim Hye-Yeon; Park Minseong; Kang Choeun; Heo Woon; Yoon Sei Mee; Lee Jinu; Kim Joo Young;
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作者单位

Yonsei Univ Dept Pharmacol Coll Med Seoul 03080 South Korea|Yonsei Univ Brain Korea 21 Plus Project Med Sci Coll Med Seoul 03080 South Korea;

Yonsei Univ Dept Pharmacol Coll Med Seoul 03080 South Korea|Yonsei Univ Brain Korea 21 Plus Project Med Sci Coll Med Seoul 03080 South Korea;

Yonsei Univ Dept Pharmacol Coll Med Seoul 03080 South Korea|Yonsei Univ Brain Korea 21 Plus Project Med Sci Coll Med Seoul 03080 South Korea;

Yonsei Univ Dept Pharmacol Coll Med Seoul 03080 South Korea|Yonsei Univ Brain Korea 21 Plus Project Med Sci Coll Med Seoul 03080 South Korea;

Yonsei Univ Coll Pharm Yonsei Inst Pharmaceut Sci Incheon 21983 South Korea;

Yonsei Univ Coll Pharm Yonsei Inst Pharmaceut Sci Incheon 21983 South Korea;

Yonsei Univ Dept Pharmacol Coll Med Seoul 03080 South Korea|Yonsei Univ Brain Korea 21 Plus Project Med Sci Coll Med Seoul 03080 South Korea;

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正文语种 eng
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关键词
Rituximab; O-GlcNAc; Production yield; Thiamet G; ADCC; CDC; Thermal stability;

机译：Rituximab;O-Glcnac;产量;噻虫G;ADCC;CDC;热稳定性;

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O-GlcNAcylation of light chain serine 12 mediates rituximab production doubled by thiamet G

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