Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 BCMB Allied Program, Weill Cornell Medical College, New York, NY 10065.
Mol Biol Cell. 2013 Dec;24(23):3736-45. doi: 10.1091/mbc.E13-07-0408. Epub 2013 Oct 2.
Macroendocytic vacuoles formed by phagocytosis, or the live-cell engulfment program entosis, undergo sequential steps of maturation, leading to the fusion of lysosomes that digest internalized cargo. After cargo digestion, nutrients must be exported to the cytosol, and vacuole membranes must be processed by mechanisms that remain poorly defined. Here we find that phagosomes and entotic vacuoles undergo a late maturation step characterized by fission, which redistributes vacuolar contents into lysosomal networks. Vacuole fission is regulated by the serine/threonine protein kinase mammalian target of rapamycin complex 1 (mTORC1), which localizes to vacuole membranes surrounding engulfed cells. Degrading engulfed cells supply engulfing cells with amino acids that are used in translation, and rescue cell survival and mTORC1 activity in starved macrophages and tumor cells. These data identify a late stage of phagocytosis and entosis that involves processing of large vacuoles by mTOR-regulated membrane fission.
吞噬作用形成的大胞饮泡，或活细胞摄取程序细胞自噬，经历连续的成熟步骤，导致溶酶体融合以消化内化的货物。在货物消化后，必须将营养物质输出到细胞质中，并且必须通过仍然定义不明确的机制处理空泡膜。在这里，我们发现吞噬体和自噬小泡经历了一个晚期成熟阶段，其特征是分裂，将空泡内容物重新分配到溶酶体网络中。空泡分裂受到丝氨酸/苏氨酸蛋白激酶哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）的调节，该蛋白定位于被吞噬细胞周围的空泡膜上。降解被吞噬的细胞为吞噬细胞提供用于翻译的氨基酸，并挽救饥饿的巨噬细胞和肿瘤细胞中的细胞存活和 mTORC1 活性。这些数据确定了吞噬作用和自噬的晚期阶段，该阶段涉及 mTOR 调节的膜分裂对大空泡的处理。
