mTOR-Controlled Autophagy Requires Intracellular Ca²⁺ Signaling

Autophagy is a lysosomal degradation pathway important for cellular homeostasis and survival. Inhibition of the mammalian target of rapamycin (mTOR) is the best known trigger for autophagy stimulation. In addition, intracellular Ca2+ regulates autophagy, but its exact role remains ambiguous. Here, we report that the mTOR inhibitor rapamycin, while enhancing autophagy, also remodeled the intracellular Ca2+-signaling machinery. These alterations include a) an increase in the endoplasmic-reticulum (ER) Ca2+-store content, b) a decrease in the ER Ca2+-leak rate, and c) an increased Ca2+ release through the inositol 1,4,5-trisphosphate receptors (IP3Rs), the main ER-resident Ca2+-release channels. Importantly, buffering cytosolic Ca2+ with BAPTA impeded rapamycin-induced autophagy. These results reveal intracellular Ca2+ signaling as a crucial component in the canonical mTOR-dependent autophagy pathway.

细胞自噬（Autophagy）是一类对细胞稳态与存活至关重要的溶酶体降解途径。哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）的抑制是目前已知最明确的自噬激活触发因素。此外，细胞内钙离子（intracellular Ca2+）可调控自噬进程，但其确切作用仍不明确。本研究发现，mTOR抑制剂雷帕霉素在增强自噬的同时，还重塑了细胞内钙信号转导机制。这些改变包括：a) 内质网（ER）钙库储存容量升高；b) 内质网钙泄漏速率降低；c) 作为主要内质网驻留钙释放通道的肌醇1,4,5-三磷酸受体（inositol 1,4,5-trisphosphate receptors, IP3Rs）介导的钙释放增加。值得注意的是，使用BAPTA螯合胞质钙离子会阻碍雷帕霉素诱导的自噬。上述结果证实，细胞内钙信号转导是经典mTOR依赖型自噬通路中的关键组成部分。