ABSTRACT

Lysosomes are digestive organelles in cells containing many hydrolases, and also serve as a signaling hub to integrate intracellular and extracellular inputs; therefore, the integrity of lysosomes is critical for cellular homeostasis. Many agents and conditions can damage lysosomal membranes, which lead to leakage of lysosomal acidic contents into the cytosol thus becoming harmful for cells. Accordingly, cells have developed several defense systems to cope with damaged lysosomes, but underlying mechanisms of each system and their cross-talks are unclear. In our recent study, we found that a master transcription factor regulating autophagy and lysosomal biogenesis, TFEB (transcription factor EB) is activated during lysosomal damage, and this activation depends on an autophagy-independent function of lipidated LC3, which localizes on lysosomes. We further showed that this regulatory mechanism is essential to prevent the progression of the crystal nephropathy that accompanies lysosomal damage.

摘要

溶酶体是细胞中含有多种水解酶的消化细胞器，也是整合细胞内和细胞外输入的信号枢纽；因此，溶酶体的完整性对于细胞稳态至关重要。许多试剂和条件会损坏溶酶体膜，导致溶酶体酸性内容物泄漏到细胞质中，从而对细胞有害。因此，细胞已经开发出多种防御系统来应对受损的溶酶体，但每个系统的潜在机制及其相互影响尚不清楚。在我们最近的研究中，我们发现调节自噬和溶酶体生物发生的主要转录因子 TFEB（转录因子 EB）在溶酶体损伤期间被激活，这种激活依赖于脂化 LC3 的自噬独立功能，该功能位于溶酶体上。