Department of Obstetrics and Gynecology, C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA.
Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
J Cell Biol. 2025 Feb 3;224(2). doi: 10.1083/jcb.202312099. Epub 2024 Nov 18.
Separase regulates multiple aspects of the metaphase-to-anaphase transition. Separase cleaves cohesin to allow chromosome segregation and localizes to vesicles to promote exocytosis. The anaphase-promoting complex/cyclosome (APC/C) activates separase by ubiquitinating its inhibitory chaperone, securin, triggering its degradation. How this pathway controls the exocytic function of separase is unknown. During meiosis I, securin is degraded over several minutes, while separase rapidly relocalizes from kinetochore structures at the spindle and cortex to sites of action on chromosomes and vesicles at anaphase onset. The loss of cohesin coincides with the relocalization of separase to the chromosome midbivalent at anaphase onset. APC/C depletion prevents separase relocalization, while securin depletion causes precocious separase relocalization. Expression of non-degradable securin inhibits chromosome segregation, exocytosis, and separase localization to vesicles but not to the anaphase spindle. We conclude that APC/C-mediated securin degradation controls separase localization. This spatiotemporal regulation will impact the effective local concentration of separase for more precise targeting of substrates in anaphase.
分离酶调节着有丝分裂向后期转变的多个方面。分离酶切割黏连蛋白以允许染色体分离，并定位于小泡以促进胞吐作用。后期促进复合物/周期蛋白（APC/C）通过泛素化其抑制性伴侣 securin 来激活分离酶，引发其降解。这条途径如何控制分离酶的胞吐功能尚不清楚。在减数分裂 I 中，securin 在几分钟内降解，而分离酶则迅速从纺锤体和皮质处的动粒结构重新定位到后期起始时染色体和小泡上的作用部位。黏连蛋白的丢失与分离酶在后期起始时重新定位到染色体中板相对应。APC/C 消耗阻止了分离酶的重新定位，而 securin 的消耗导致分离酶过早重新定位。不可降解 securin 的表达抑制了染色体分离、胞吐作用以及分离酶向小泡的定位，但不抑制其向后期纺锤体的定位。我们得出结论，APC/C 介导的 securin 降解控制着分离酶的定位。这种时空调节将影响分离酶在后期用于更精确靶向底物的有效局部浓度。
