Pechincha Catarina, Groessl Sven, Kalis Robert, de Almeida Melanie, Zanotti Andrea, Wittmann Marten, Schneider Martin, de Campos Rafael P, Rieser Sarah, Brandstetter Marlene, Schleiffer Alexander, Müller-Decker Karin, Helm Dominic, Jabs Sabrina, Haselbach David, Lemberg Marius K, Zuber Johannes, Palm Wilhelm
Cell Signaling and Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany.
Science. 2022 Oct 7;378(6615):eabn5637. doi: 10.1126/science.abn5637.
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. 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 because of 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.
哺乳动物细胞可以通过巨胞饮作用和细胞外蛋白质的溶酶体分解来生成氨基酸，癌细胞利用这一过程在营养匮乏的肿瘤中生长。通过在特定营养条件下进行基因筛选，我们鉴定出了LYSET，这是一种跨膜蛋白（TMEM251），当细胞消耗细胞外蛋白质时选择性需要它。我们发现LYSET在高尔基体中与N-乙酰葡糖胺-1-磷酸转移酶结合，该酶通过磷酸甘露糖修饰将分解代谢酶靶向运送到溶酶体。没有LYSET，由于亲水性跨膜结构域，N-乙酰葡糖胺-1-磷酸转移酶不稳定。因此，缺乏LYSET的细胞溶酶体酶耗尽，并且在巨胞饮和自噬货物的周转方面受损。因此，LYSET代表溶酶体酶运输途径的核心成分，是遗传性溶酶体贮积症发病机制的基础，并且可能是抑制癌症代谢适应的一个靶点。
