Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability.
Lysosomal degradation ensures accurate chromosomal segregation to prevent chromosomal instability.
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溶酶体降解确保准确的染色体分离，以防止染色体不稳定。
DOI：
10.1080/15548627.2020.1764727
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发表时间：
2021-03
期刊：
影响因子：
13.3
通讯作者：
Mauvezin C
中科院分区：
文献类型：
--
作者：
Almacellas E;Pelletier J;Day C;Ambrosio S;Tauler A;Mauvezin C
溶酶体作为主要的降解细胞器，是包括大自噬在内的不同聚合途径的终点。迄今为止，溶酶体的降解功能主要是在间期细胞中研究的，而它们在有丝分裂中的作用仍然存在争议。有丝分裂决定了遗传物质在世代之间的忠实传递，有丝分裂的扰动导致染色体不稳定，这是癌症的标志。迄今为止，正确的有丝分裂进程依赖于有丝分裂因子的精心降解，这主要归因于遍在蛋白触发的蛋白酶体依赖性降解。在这里，我们表明，有丝分裂转换也依赖于溶酶体依赖性降解，作为损伤的溶酶体增加有丝分裂时间，并导致有丝分裂错误，从而促进染色体不稳定。此外，我们确定了几个假定的溶酶体有丝分裂细胞的目标。其中，WAPL，一种粘附蛋白调节蛋白，作为一种新的SQSTM 1相互作用蛋白，靶向溶酶体降解。最后，我们的特点是一个非典型的核表型，环形核，作为一种新的生物标志物的遗传毒性筛选。我们的研究结果建立了溶酶体依赖性降解作为一个必不可少的事件，以防止染色体不稳定。缩略语：3D立体：三维的; APC/C：后期促进复合物; ARL8B：ADP核糖基化因子，如GT3 - 8 B; ATG：自噬相关; BORC：BLOC-1-相关复合物; CDK：细胞周期蛋白依赖性激酶; CENPE：着丝粒蛋白E; CIN：染色体不稳定性; ConcA：康卡霉素A; CQ：氯喹; DAPI：4，6-二脒基-2-亚戊醇; FTI：法尼基转移酶抑制剂; GFP：绿色荧光蛋白; H2 B：组蛋白2B; KIF：驱动蛋白家族成员; LAMP 2：溶酶体相关膜蛋白2; MAP 1 LC 3/LC 3：微管相关蛋白1轻链3; MEF：小鼠胚胎成纤维细胞; MTOR：雷帕霉素激酶的机制靶点; PDS 5 B：PDS 5粘附素相关因子B; SAC：纺锤体组装检查点; PLEKHM 2：含有M2的普列克底物蛋白同源性和RUN结构域; SQSTM 1：隔离体1; TEM：透射电子显微镜; ULK 1：unc-51样自噬激活激酶1; UPS：泛素-蛋白酶体系统; v-ATPase：空泡型H+易位ATPase; WAPL：WAPL凝聚释放因子。
Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition also relies on lysosome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel SQSTM1-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent chromosomal instability. Abbreviations: 3D: three-dimensional; APC/C: anaphase-promoting complex; ARL8B: ADP ribosylation factor like GTPase 8B; ATG: autophagy-related; BORC: BLOC-one-related complex; CDK: cyclin-dependent kinase; CENPE: centromere protein E; CIN: chromosomal instability; ConcA: concanamycin A; CQ: chloroquine; DAPI: 4,6-diamidino-2-penylinole; FTI: farnesyltransferase inhibitors; GFP: green fluorescent protein; H2B: histone 2B; KIF: kinesin family member; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; PDS5B: PDS5 cohesin associated factor B; SAC: spindle assembly checkpoint; PLEKHM2: pleckstrin homology and RUN domain containing M2; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; v-ATPase: vacuolar-type H+-translocating ATPase; WAPL: WAPL cohesion release factor.
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13.3
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作者：
Araujo, Ana Rita;Gelens, Lendert;Sheriff, Rahuman S. M.;Santos, Silvia D. M.
通讯作者：
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