Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation
Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation
复制标题
DOI：
10.1038/s41467-019-14009-0
复制
发表时间：
2020-01-13
影响因子：
16.6
通讯作者：
Jaattela, Marja
中科院分区：
文献类型：
--
作者：
Hamalisto, Saara;Stahl, Jonathan Lucien;Jaattela, Marja
溶酶体是被膜包围的细胞质细胞器，充满了强大的水解酶混合物。除了降解溶酶体腔内的细胞成分外，溶酶体水解酶在递送至细胞外空间时促进组织重塑，并且在释放至细胞溶质时促进细胞死亡。在这里，我们表明，空间和时间控制的溶酶体泄漏有助于在正常哺乳动物细胞分裂的准确染色体分离。在大多数前中期，一个或多个染色质近端溶酶体泄漏，之后活性组织蛋白酶B（CTSB）定位于中期染色质并切割一小部分组蛋白H3。有丝分裂进入期间溶酶体膜的稳定或CTSB活性的抑制导致端粒相关的染色体分离缺陷显著增加，而缺乏CTSB的细胞和组织以及表达CTSB抗性组蛋白H3的细胞积累微核和其他核缺陷。这些数据表明，溶酶体渗漏和染色质相关的CTSB有助于正确的染色体分离和维持基因组的完整性。
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.