Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Dev Cell. 2019 May 20;49(4):574-589.e5. doi: 10.1016/j.devcel.2019.03.029. Epub 2019 Apr 18.
The effect of intracellular vesicle trafficking on stem-cell behavior is largely unexplored. We screened the Drosophila sorting nexins (SNXs) and discovered that one, SH3PX1, profoundly affects gut homeostasis and lifespan. SH3PX1 restrains intestinal stem cell (ISC) division through an endocytosis-autophagy network that includes Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. Blockages in this network stabilize ligand-activated EGFRs, recycling them via Rab11-dependent endosomes to the plasma membrane. This hyperactivated ERK, calcium signaling, and ER stress, autonomously stimulating ISC proliferation. The excess divisions induced epithelial stress, Yki activity, and Upd3 and Rhomboid production in enterocytes, catalyzing feedforward ISC hyperplasia. Similarly, blocking autophagy increased ERK activity in human cells. Many endocytosis-autophagy genes are mutated in cancers, most notably those enriched in microsatellite instable-high and KRAS-wild-type colorectal cancers. Disruptions in endocytosis and autophagy may provide an alternative route to RAS-ERK activation, resulting in EGFR-dependent cancers.
细胞内囊泡运输对干细胞行为的影响在很大程度上尚未被探索。我们筛选了果蝇分选连接蛋白（SNXs），发现其中一个蛋白 SH3PX1 会显著影响肠道稳态和寿命。SH3PX1 通过一个包含 Dynamin、Rab5、Rab7、Atg1、5、6、7、8a、9、12、16 和 Syx17 的内吞作用-自噬网络来抑制肠干细胞（ISC）的分裂。该网络中的阻断作用稳定了配体激活的 EGFR，通过 Rab11 依赖性内体将其再循环到质膜。这种过度激活的 ERK、钙信号和 ER 应激，自主地刺激 ISC 增殖。过度分裂导致上皮应激、Yki 活性和 Enterocytes 中 Upd3 和 Rhomboid 的产生，从而促进 ISC 过度增生。同样，阻断自噬会增加人类细胞中的 ERK 活性。许多内吞作用-自噬基因在癌症中发生突变，尤其是在微卫星不稳定高和 KRAS 野生型结直肠癌中富集的基因。内吞作用和自噬的破坏可能为 RAS-ERK 激活提供另一种途径，导致 EGFR 依赖性癌症。
