Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation

Saara Hämälistö, Jonathan Lucien Stahl, Elena Favaro, Qing Yang, Bin Liu, Line Christoffersen, Ben Loos, Claudia Guasch Boldú, Johanna A. Joyce, Thomas Reinheckel, Marin Barisic and Marja Jäättelä ()
Additional contact information
Saara Hämälistö: Danish Cancer Society Research Center
Jonathan Lucien Stahl: Danish Cancer Society Research Center
Elena Favaro: Danish Cancer Society Research Center
Qing Yang: Danish Cancer Society Research Center
Bin Liu: Danish Cancer Society Research Center
Line Christoffersen: Danish Cancer Society Research Center
Ben Loos: Stellenbosch University
Claudia Guasch Boldú: Danish Cancer Society Research Center
Johanna A. Joyce: University of Lausanne
Thomas Reinheckel: University of Freiburg
Marin Barisic: Danish Cancer Society Research Center
Marja Jäättelä: Danish Cancer Society Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14009-0

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