Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation

Abstract

Lysosomes are membrane-surrounded cytoplasmic organelles filled with a powerful cocktail of hydrolases. Besides degrading cellular constituents inside the lysosomal lumen, lysosomal hydrolases promote tissue remodeling when delivered to the extracellular space and cell death when released to the cytosol. Here, we show that spatially and temporally controlled lysosomal leakage contributes to the accurate chromosome segregation in normal mammalian cell division. One or more chromatin-proximal lysosomes leak in the majority of prometaphases, after which active cathepsin B (CTSB) localizes to the metaphase chromatin and cleaves a small subset of histone H3. Stabilization of lysosomal membranes or inhibition of CTSB activity during mitotic entry results in a significant increase in telomere-related chromosome segregation defects, whereas cells and tissues lacking CTSB and cells expressing CTSB-resistant histone H3 accumulate micronuclei and other nuclear defects. These data suggest that lysosomal leakage and chromatin-associated CTSB contribute to proper chromosome segregation and maintenance of genomic integrity.

Lipid dismantling of lens organelles for clear vision

“…This result underscores the key role of lysosomal-membrane permeabilization in physiological and developmental contexts, such as during cell division 9 or in the shrinkage of the mammary gland after lactation 10 . The authors further show that Hsf4-mediated permeabilization of the mitochondrial membrane is also required for HRASLS translocation to mitochondria in zebrafish, and that mitochondrial degradation is suppressed in Hsf4-deficient zebrafish.…”

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

“…In turn, hydrolase depletion could stem from transcriptional inhibition or from their defective trafficking to the lysosome (Kobayashi et al, 1999;Saftig and Klumperman, 2009;Sleat et al, 2013). Alternatively, it is tempting to speculate that the increased propensity of NPC lysosomes to undergo membrane damage could result in leakage of lumenal contents, including resident hydrolases, a phenomenon suggested to occur in NPC as well as other physiological and pathological contexts (Chung et al, 2016;Hämälistö et al, 2020;Maejima et al, 2013;Sakamachi et al, 2017).…”

Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability

“…Although lysosome studies are mainly focused on interphase cells, endocytic vesicles (including lysosomes) were proposed to serve as a membrane source for plasma membrane extension and retraction during mitotic transition [ 14 , 15 ]. Recently, PCM1-driven selective degradation of centriolar satellites was shown to maintain centrosome function for correct mitotic progression [ 25 ], and lysosome leakage was proposed to allow correct chromosome segregation [ 46 ]. Here, our results agree with the persistence of a robust autophagic flux and lysosomal-dependent degradation during mitosis [ 23 ].…”