School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, 80 Daehakro Bukgu, Daegu, 41566, Republic of Korea.
Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41566, Republic of Korea.
Arch Pharm Res. 2021 Jun;44(6):621-631. doi: 10.1007/s12272-021-01335-5. Epub 2021 Jun 7.
The maintenance of lysosomal integrity is essential for lysosome function and cell fate. Damaged lysosomes are degraded by lysosomal autophagy, lysophagy. The mechanism underlying lysophagy remains largely unknown; this study aimed to contribute to the understanding of this topic. A cell-based screening system was used to identify novel lysophagy modulators. Triamterene (6-phenylpteridine-2,4,7-triamine) was identified as one of the most potent lysophagy inducers from the screening process. We found that triamterene causes lysosomal rupture without affecting other cellular organelles and increases autophagy flux in HepG2 cells. Damaged lysosomes in triamterene-treated cells were removed by autophagy-mediated pathway, which was inhibited by depletion of the autophagy regulator, ATG5 or SQSTM1. In addition, treatment of triamterene decreased the integrity of lysosome and cell viability, which were rescued by removing the triamterene treatment in HepG2 cells. Hence, our data suggest that triamterene is a novel lysophagy inducer through the disruption of lysosomal integrity.
溶酶体完整性的维持对于溶酶体功能和细胞命运至关重要。受损的溶酶体通过溶酶体自噬（溶酶体吞噬作用）进行降解。溶酶体吞噬作用的机制在很大程度上尚不清楚；本研究旨在为这一主题的理解做出贡献。本研究使用基于细胞的筛选系统来鉴定新型溶酶体吞噬调节剂。在筛选过程中，发现曲安奈德（6-苯基蝶啶-2,4,7-三胺）是最有效的溶酶体吞噬诱导剂之一。我们发现，曲安奈德在不影响其他细胞细胞器的情况下引起溶酶体破裂，并增加 HepG2 细胞中的自噬通量。在曲安奈德处理的细胞中，受损的溶酶体通过自噬介导的途径被清除，该途径可被自噬调节剂 ATG5 或 SQSTM1 的消耗所抑制。此外，曲安奈德处理降低了溶酶体的完整性和细胞活力，而在 HepG2 细胞中去除曲安奈德处理可挽救这一情况。因此，我们的数据表明，曲安奈德通过破坏溶酶体完整性成为一种新型的溶酶体吞噬诱导剂。
