Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury
Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury
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DOI：
10.1038/emboj.2013.171
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发表时间：
2013-08-28
期刊：
影响因子：
11.4
通讯作者：
Yoshimori, Tamotsu
中科院分区：
文献类型：
--
作者：
Maejima, Ikuko;Takahashi, Atsushi;Yoshimori, Tamotsu
多种原因，包括病原体入侵或矿物质晶体如二氧化硅和尿酸盐（MSU）的摄取，威胁细胞溶酶体破裂，这可能导致氧化应激，炎症和细胞凋亡或坏死。在这里，我们证明了溶酶体被选择性地隔离的自噬，当被MSU，二氧化硅，或lysosomotropic试剂L-亮氨酰-L-亮氨酸甲酯（LLOMe）损坏。自噬机制仅在受损的溶酶体上被招募，然后被自噬体吞噬。以自噬依赖的方式，受损溶酶体的低pH和降解能力得以恢复。在溶酶体损伤的条件下，自噬的丧失导致体外溶酶体生物合成的抑制和体内急性肾损伤的恶化。因此，我们提出，隔离受损的溶酶体的自噬是必不可少的细胞和组织的稳态。
Diverse causes, including pathogenic invasion or the uptake of mineral crystals such as silica and monosodium urate (MSU), threaten cells with lysosomal rupture, which can lead to oxidative stress, inflammation, and apoptosis or necrosis. Here, we demonstrate that lysosomes are selectively sequestered by autophagy, when damaged by MSU, silica, or the lysosomotropic reagent L-Leucyl-L-leucine methyl ester (LLOMe). Autophagic machinery is recruited only on damaged lysosomes, which are then engulfed by autophagosomes. In an autophagy-dependent manner, low pH and degradation capacity of damaged lysosomes are recovered. Under conditions of lysosomal damage, loss of autophagy causes inhibition of lysosomal biogenesis in vitro and deterioration of acute kidney injury in vivo. Thus, we propose that sequestration of damaged lysosomes by autophagy is indispensable for cellular and tissue homeostasis.