Glycoforms of human prostate-specific membrane antigen (PSMA) in human cells and prostate tissue.
Glycoforms of human prostate-specific membrane antigen (PSMA) in human cells and prostate tissue.
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DOI：
10.1002/pros.24254
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发表时间：
2022-01
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--
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N-糖基化是一种普遍存在的可变的翻译后修饰，其调节分泌和膜相关蛋白的生理功能，并且糖基化途径的失调通常与癌症生长和转移相关。前列腺特异性膜抗原（PSMA）是前列腺癌成像和治疗的既定生物标志物。使用质谱分析PSMA在昆虫、人胚肾和前列腺癌细胞中以及在免疫亲和富集后在前列腺组织中的位点特异性糖型的分布。虽然在昆虫细胞中表达的重组PSMA主要由少甘露糖和高甘露糖聚糖修饰，但在来自人细胞和组织的样品中检测到复合、杂合和高甘露糖聚糖。我们注意到PSMA表面上糖型的有趣空间分布-高甘露糖聚糖是面向质膜的N459、N476和N638序列子处的主要糖型，而位于暴露的顶端PSMA结构域的N121、N195和N336位点主要携带复合聚糖。在前序列中存在高甘露糖糖型可能是由于合成复合物结构所需的糖合成途径的酶的有限接近。与膜近端位点的有限可及性一致，在最靠近膜的N51位点未观察到糖基化。我们的研究提出了在细胞系和前列腺组织中观察到的PSMA糖型的初步描述性分析。这将有望刺激进一步研究PSMA糖型的背景下，肿瘤分期，前列腺肿瘤的非侵入性检测，以及糖型的影响，PSMA的理化和酶的特性，在组织特异性的方式。
N-glycosylation is a ubiquitous and variable posttranslational modification that regulates physiological functions of secretory and membrane-associated proteins and the dysregulation of glycosylation pathways is often associated with cancer growth and metastasis. Prostate-specific membrane antigen (PSMA) is an established biomarker for prostate cancer imaging and therapy. Mass spectrometry was used to analyze the distribution of the site-specific glycoforms of PSMA in insect, human embryonic kidney, and prostate cancer cells, and in prostate tissue upon immunoaffinity enrichment. While recombinant PSMA expressed in insect cells was decorated mainly by paucimannose and high mannose glycans, complex, hybrid, and high mannose glycans were detected in samples from human cells and tissue. We noted an interesting spatial distribution of the glycoforms on the PSMA surface—high mannose glycans were the dominant glycoforms at the N459, N476, and N638 sequons facing the plasma membrane, while the N121, N195, and N336 sites, located at the exposed apical PSMA domain, carried primarily complex glycans. The presence of high mannose glycoforms at the former sequons likely results from the limited access of enzymes of the glycosynthetic pathway required for the synthesis of the complex structures. In line with the limited accessibility of membrane-proximal sites, no glycosylation was observed at the N51 site positioned closest to the membrane. Our study presents initial descriptive analysis of the glycoforms of PSMA observed in cell lines and in prostate tissue. It will hopefully stimulate further research into PSMA glycoforms in the context of tumor staging, noninvasive detection of prostate tumors, and the impact of glycoforms on physicochemical and enzymatic characteristics of PSMA in a tissue-specific manner.
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