Updates on the study of lysosomal protein dynamics: possibilities for the clinic

The lysosome is the main degradative organelle of almost all mammalian cells, fulfilling important functions in macromolecule recycling, metabolism, and signaling. Lysosomal dysfunction is connected to a continuously growing number of pathologic conditions, and lysosomal proteins present potential biomarkers for a variety of diseases. Therefore, there is an increasing interest in their analysis in patient samples. We provide an overview of OMICs studies which identified lysosomal proteins as potential biomarkers for pathological conditions, covering proteomics, genomics, and transcriptomics approaches, identified through PubMed searches. With respect to discovery proteomics analyses, mainly lysosomal luminal and associated proteins were detected, while membrane proteins were found less frequently. Comprehensive coverage of the lysosomal proteome was only achieved by ultra-deep-coverage studies, but targeted approaches allowed for the reproducible quantification of lysosomal proteins in diverse sample types. The low abundance of lysosomal proteins complicates their reproducible analysis in patient samples. Whole proteome shotgun analyses fail in many instances to cover the lysosomal proteome, which is due to under-sampling and/or a lack of sensitivity. With the current state of the art, targeted proteomics assays provide the best performance for the characterization of lysosomal proteins in patient samples.

溶酶体（lysosome）是几乎所有哺乳动物细胞的主要降解细胞器，在大分子回收、代谢与信号传导过程中发挥关键功能。溶酶体功能异常与日益增多的病理状态密切相关，而溶酶体蛋白可作为多种疾病的潜在生物标志物。因此，针对患者样本中溶酶体蛋白的分析研究正受到越来越多的关注。本研究综述了通过PubMed检索得到的、将溶酶体蛋白鉴定为病理状态潜在生物标志物的组学（OMICs）研究，涵盖蛋白质组学、基因组学与转录组学技术手段。在发现蛋白质组学分析中，研究人员主要检测到溶酶体腔室蛋白及其结合蛋白，而膜蛋白的检出率相对较低。仅通过超深度覆盖度研究才能实现溶酶体蛋白质组的全面覆盖，而靶向技术则可在多种样本类型中实现溶酶体蛋白的可重复定量。溶酶体蛋白的低丰度特性使得其在患者样本中的可重复分析颇具挑战。全蛋白质组鸟枪法分析在多数情况下无法覆盖溶酶体蛋白质组，这一问题源于采样不足和/或灵敏度不足。就当前技术水平而言，靶向蛋白质组学检测是实现患者样本中溶酶体蛋白表征的最优方案。