Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury.
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.
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
Ikuko
I
Maejima
Atsushi
A
Takahashi
Hiroko
H
Omori
Tomonori
T
Kimura
Yoshitsugu
Y
Takabatake
Tatsuya
T
Saitoh
Akitsugu
A
Yamamoto
Maho
M
Hamasaki
Takeshi
T
Noda
Yoshitaka
Y
Isaka
Tamotsu
T
Yoshimori
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D002460:Cell Line / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D033461:Hyperuricemia / Q000503:physiopathology; D007684:Kidney Tubules / Q000503:physiopathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells / Q000187:drug effects; D010588:Phagosomes / Q000502:physiology; D014527:Uric Acid / Q000494:pharmacology
C502661:Atg7 protein, mouse; D004151:Dipeptides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C045139:leucyl-leucine-methyl ester; D049452:Green Fluorescent Proteins; D014527:Uric Acid; D000071193:Autophagy-Related Protein 7