Department of Biology, University of Fribourg, 1700, Fribourg, Switzerland.
Department of Biomedical Sciences of Cells and Systems, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.
Nat Commun. 2022 Aug 10;13(1):4685. doi: 10.1038/s41467-022-32487-7.
The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation, supporting anabolic reactions and inhibiting catabolic pathways like autophagy. Its hyperactivation is a frequent event in cancer promoting tumor cell proliferation. Several intracellular membrane-associated mTORC1 pools have been identified, linking its function to distinct subcellular localizations. Here, we characterize the N-terminal kinase-like protein SCYL1 as a Golgi-localized target through which mTORC1 controls organelle distribution and extracellular vesicle secretion in breast cancer cells. Under growth conditions, SCYL1 is phosphorylated by mTORC1 on Ser754, supporting Golgi localization. Upon mTORC1 inhibition, Ser754 dephosphorylation leads to SCYL1 displacement to endosomes. Peripheral, dephosphorylated SCYL1 causes Golgi enlargement, redistribution of early and late endosomes and increased extracellular vesicle release. Thus, the mTORC1-controlled phosphorylation status of SCYL1 is an important determinant regulating subcellular distribution and function of endolysosomal compartments. It may also explain the pathophysiology underlying human genetic diseases such as CALFAN syndrome, which is caused by loss-of-function of SCYL1.
雷帕霉素靶蛋白复合物 1（mTORC1）是细胞生长和增殖的主要调节因子，支持合成代谢反应，并抑制自噬等分解代谢途径。其过度激活是促进肿瘤细胞增殖的癌症中的常见事件。已经鉴定出几种细胞内膜相关的 mTORC1 池，将其功能与不同的亚细胞定位联系起来。在这里，我们将 N 端激酶样蛋白 SCYL1 表征为高尔基定位的靶标，通过该靶标 mTORC1 控制乳腺癌细胞中的细胞器分布和细胞外囊泡分泌。在生长条件下，mTORC1 将 SCYL1 磷酸化 Ser754，支持高尔基定位。在 mTORC1 抑制后，Ser754 去磷酸化导致 SCYL1 移位到内体。外周去磷酸化的 SCYL1 导致高尔基增大、早期和晚期内体重新分布以及细胞外囊泡释放增加。因此，mTORC1 控制的 SCYL1 磷酸化状态是调节内体溶酶体区室的亚细胞分布和功能的重要决定因素。它也可能解释人类遗传疾病（如 CALFAN 综合征）的病理生理学基础，CALFAN 综合征是由 SCYL1 功能丧失引起的。
