The PSMA8 subunit of the spermatoproteasome is essential for proper meiotic exit and mouse fertility
The PSMA8 subunit of the spermatoproteasome is essential for proper meiotic exit and mouse fertility
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DOI：
10.1371/journal.pgen.1008316
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发表时间：
2019-08-01
期刊：
影响因子：
4.5
通讯作者：
Pendas, Alberto M.
中科院分区：
文献类型：
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作者：
Gomez-H, Laura;Felipe-Medina, Natalia;Pendas, Alberto M.
泛素蛋白酶体系统通过与联会复合体的结合来调节酵母中的减数分裂重组，联会复合体是一种“拉链”状结构，在减数分裂前期 I 期间将同源染色体对保持在联会中。在哺乳动物中，蛋白酶体激活剂亚基 PA200 在体细胞 DNA 双链断裂修复期间和精子发生过程中的组蛋白替换期间以乙酰化组蛋白为目标进行降解。我们研究了睾丸特异性蛋白酶体亚基 α 4s (PSMA8) 在精子发生过程中的作用，发现 PSMA8 位于并依赖于联会复合体的中心区域。因此，突触缺陷小鼠表现出 PSMA8 的离域化。此外，尽管 Psma8 缺陷小鼠精通减数分裂同源重组，但除已知的底物乙酰化组蛋白外，几个关键减数分裂参与者的蛋白质稳态也发生了改变，蛋白质组学方法已显示这些参与者与 PSMA8 相互作用，例如 SYCP3、SYCP1、CDK1 和 TRIP13。这些改变导致精母细胞在中期 I 和 II 中积累，要么大量进入细胞凋亡，要么产生少量异常的圆形精子细胞，这些精子细胞在组蛋白替代发生之前凋亡。待降解的蛋白质由一种称为泛素的小蛋白质标记。对一些蛋白质添加小的修饰（乙酰基）也会促进它们被蛋白酶体降解。蛋白质的蛋白酶体降解是许多发育程序的重要机制，包括配子发生，二倍体细胞产生单倍体细胞或配子（精子或卵子）的过程。这种基因组减少发生的机制称为减数分裂。在此，我们报告了对一种名为 PSMA8 的蛋白质的研究，该蛋白质是脊椎动物睾丸蛋白酶体的特异性蛋白质。使用小鼠作为模型，我们发现 PSMA8 的缺失会导致男性不育。通过免疫共沉淀耦合质谱法，我们鉴定了大量新型 PSMA8 相互作用蛋白。除了精子蛋白酶体的已知底物乙酰化组蛋白之外，我们将功能分析的重点放在积累的几个关键减数分裂蛋白上，例如 SYCP3、SYCP1、CDK1 和 TRIP13。我们认为，这些重要蛋白质积累的改变会导致减数分裂的不平衡，从而在中期 I 和 II 中产生凋亡的精母细胞，以及在到达该阶段后很快死亡的早期精子细胞。
The ubiquitin proteasome system regulates meiotic recombination in yeast through its association with the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I. In mammals, the proteasome activator subunit PA200 targets acetylated histones for degradation during somatic DNA double strand break repair and during histone replacement during spermiogenesis. We investigated the role of the testis-specific proteasomal subunit alpha 4s (PSMA8) during spermatogenesis, and found that PSMA8 was localized to and dependent on the central region of the synaptonemal complex. Accordingly, synapsis-deficient mice show delocalization of PSMA8. Moreover, though Psma8-deficient mice are proficient in meiotic homologous recombination, there are alterations in the proteostasis of several key meiotic players that, in addition to the known substrate acetylated histones, have been shown by a proteomic approach to interact with PSMA8, such as SYCP3, SYCP1, CDK1 and TRIP13. These alterations lead to an accumulation of spermatocytes in metaphase I and II which either enter massively into apoptosis or give rise to a low number of aberrant round spermatids that apoptose before histone replacement takes place.Author summary Proteins within the cells that are unnecessary or damaged are degraded by a large protein complex named the proteasome. The proteins to be degraded are marked by a small protein called ubiquitin. The addition of a small modification (acetyl group) to some proteins also promotes their degradation by the proteasome. Proteasomal degradation of proteins is an essential mechanism for many developmental programs including gametogenesis, a process whereby a diploid cell produces a haploid cell or gamete (sperm or egg). The mechanism by which this genome reduction occurs is called meiosis. Here, we report the study of a protein, named PSMA8 that is specific for the testis proteasome in vertebrates. Using the mouse as a model, we show that loss of PSMA8 leads to infertility in males. By co-immunoprecipitation-coupled mass spectroscopy we identified a large list of novel PSMA8 interacting proteins. We focused our functional analysis on several key meiotic proteins which were accumulated such as SYCP3, SYCP1, CDK1 and TRIP13 in addition to the known substrate of the spermatoproteasome, the acetylated histones. We suggest that the altered accumulation of these important proteins causes a disequilibrium of the meiotic division that produces apoptotic spermatocytes in metaphase I and II and also early spermatids that die soon after reaching this stage.