School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, People's Republic of China.
Centre for Cell and Developmental Biology, State Key Laboratory of Agrobiotechnology, School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China.
Sci Rep. 2020 Nov 26;10(1):20719. doi: 10.1038/s41598-020-77620-y.
Transient receptor potential channel M2 (TRPM2) is a Ca-permeable channel that is activated by reactive oxygen species (ROS). In many cell types, ROS activate TRPM2 to induce excessive Ca influx, resulting in Ca overload and consequent cell death. Recent studies suggest that TRPM2 may also regulate autophagy in pericytes and cancer cells by acting on the early step of autophagy, i.e. autophagic induction. However, there is no report on the role of TRPM2 in autophagic degradation, which is the late stage of autophagy. In the present study, we found abundant TRPM2 expression in lysosomes/autolysosomes in the primary cultured mouse aortic smooth muscle cells (mASMCs). Nutrient starvation stimulated autophagic flux in mASMCs mainly by promoting autophagic degradation. This starvation-induced autophagic degradation was reduced by TRPM2 knockout. Importantly, starvation-induced lysosomal/autolysosomal acidification and cell death were also substantially reduced by TRPM2 knockout. Taken together, the present study uncovered a novel mechanism that lysosomal TRPM2 facilitates lysosomal acidification to stimulate excessive autolysosome degradation and consequent cell death.
瞬时受体电位通道 M2（TRPM2）是一种由活性氧物质（ROS）激活的 Ca 通透性通道。在许多细胞类型中，ROS 激活 TRPM2 以诱导过量的 Ca 内流，导致 Ca 过载和随后的细胞死亡。最近的研究表明，TRPM2 也可能通过作用于自噬的早期步骤，即自噬诱导，来调节周细胞和癌细胞中的自噬。然而，目前尚无关于 TRPM2 在自噬降解（自噬的晚期阶段）中的作用的报道。在本研究中，我们发现大量 TRPM2 表达于原代培养的小鼠主动脉平滑肌细胞（mASMCs）的溶酶体/自溶酶体中。营养饥饿主要通过促进自噬降解来刺激 mASMCs 中的自噬流。TRPM2 敲除减少了这种饥饿诱导的自噬降解。重要的是，TRPM2 敲除还显著减少了饥饿诱导的溶酶体/自溶酶体酸化和细胞死亡。综上所述，本研究揭示了一个新的机制，即溶酶体 TRPM2 促进溶酶体酸化以刺激过度的自溶酶体降解并随后导致细胞死亡。
