通过在确定营养条件下的遗传筛选，研究人员确定了LYSET的特征，这是一个跨膜蛋白（TMEM251），当细胞消耗细胞外蛋白质时，会选择性地需要它。LYSET被发现在高尔基体中与GlcNAc-1-磷酸转移酶相关联，后者通过甘露糖-6-磷酸修饰将分解酶定向到溶酶体中。如果没有LYSET，GlcNAc-1-磷酸转移酶是不稳定的，因为它有一个亲水的跨膜域。因此，LYSET缺陷的细胞被耗尽了溶酶体酶，并在巨胞饮和自噬货物的周转方面受到损害。因此，LYSET代表了溶酶体酶运输途径的一个核心成分，是遗传性溶酶体储存障碍病理机制的基础，并可能代表一个抑制癌症中代谢适应的靶标。
据悉，哺乳动物细胞可以通过巨胞饮作用和溶酶体对细胞外蛋白质的分解产生氨基酸，癌细胞利用这一点在营养不良的肿瘤中生长。
附：英文原文
Title: Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins
Author: Catarina Pechincha, Sven Groessl, Robert Kalis, Melanie de Almeida, Andrea Zanotti, Marten Wittmann, Martin Schneider, Rafael P. de Campos, Sarah Rieser, Marlene Brandstetter, Alexander Schleiffer, Karin Müller-Decker, Dominic Helm, Sabrina Jabs, David Haselbach, Marius K. Lemberg, Johannes Zuber, Wilhelm Palm
Issue&Volume: 2022-09-08
Abstract: Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins, which is exploited by cancer cells to grow in nutrient-poor tumors. Here, through genetic screens in defined nutrient conditions we characterized LYSET, a transmembrane protein (TMEM251) selectively required when cells consume extracellular proteins. LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase, which targets catabolic enzymes to lysosomes through mannose-6-phosphate modification. Without LYSET, GlcNAc-1-phosphotransferase was unstable owing to a hydrophilic transmembrane domain. Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. Thus, LYSET represents a core component of the lysosomal enzyme trafficking pathway, underlies the pathomechanism for hereditary lysosomal storage disorders, and may represent a target to suppress metabolic adaptations in cancer.
DOI: abn5637
Source: https://www.science.org/doi/10.1126/science.abn5637