VCP promotes tTAF-target gene expression and spermatocyte differentiation by downregulating mono-ubiquitylated H2A.
VCP promotes tTAF-target gene expression and spermatocyte differentiation by downregulating mono-ubiquitylated H2A.
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VCP通过下调单一泛素化的H2A促进tTAF靶基因表达和精母细胞分化。
DOI：
10.1242/dev.201557
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发表时间：
2023-07-15
期刊：
影响因子：
4.6
通讯作者：
Bohnert, K. Adam
中科院分区：
文献类型：
--
作者：
Butsch, Tyler J.;Dubuisson, Olga;Johnson, Alyssa E.;Bohnert, K. Adam
Valosin-containing protein （VCP）通过结合和提取泛素化货物来调节蛋白质稳态。VCP主要在衰老和疾病背景下进行研究，但它也影响生殖细胞发育。然而，VCP在种系中的精确分子功能，特别是在男性中，知之甚少。利用果蝇雄性生殖系作为模型系统，我们发现当生殖细胞进入减数分裂精细胞阶段时，VCP从细胞质转移到细胞核。重要的是，VCP的核易位似乎是睾丸特异性tbp相关因子（tTAFs）刺激的驱动精母细胞分化的一个关键事件。VCP促进了几个tTAF靶基因的表达，VCP敲低，与tTAF功能丧失一样，导致细胞在减数分裂早期停滞。在分子水平上，VCP活性通过下调减数分裂过程中抑制性组蛋白修饰单泛素化H2A （H2Aub）来支持精母细胞基因表达。值得注意的是，通过实验阻断VCP-RNAi睾丸中的H2Aub足以克服减数分裂阻滞表型，并在精细胞阶段促进发育。总的来说，我们的数据突出了VCP作为tTAFs的下游效应物，下调H2Aub以促进减数分裂进程。摘要：在果蝇雄性种系中，VCP在减数分裂期间从细胞质转移到细胞核，并指导单泛素化H2A的下调，以支持精母细胞基因表达和分化。
Valosin-containing protein (VCP) binds and extracts ubiquitylated cargo to regulate protein homeostasis. VCP has been studied primarily in aging and disease contexts, but it also affects germline development. However, the precise molecular functions of VCP in the germline, particularly in males, are poorly understood. Using the Drosophila male germline as a model system, we find that VCP translocates from the cytosol to the nucleus as germ cells transition into the meiotic spermatocyte stage. Importantly, nuclear translocation of VCP appears to be one crucial event stimulated by testis-specific TBP-associated factors (tTAFs) to drive spermatocyte differentiation. VCP promotes the expression of several tTAF-target genes, and VCP knockdown, like tTAF loss of function, causes cells to arrest in early meiotic stages. At a molecular level, VCP activity supports spermatocyte gene expression by downregulating a repressive histone modification, mono-ubiquitylated H2A (H2Aub), during meiosis. Remarkably, experimentally blocking H2Aub in VCP-RNAi testes is sufficient to overcome the meiotic-arrest phenotype and to promote development through the spermatocyte stage. Collectively, our data highlight VCP as a downstream effector of tTAFs that downregulates H2Aub to facilitate meiotic progression. Summary: In the Drosophila male germline, VCP translocates from the cytosol to the nucleus during meiosis and directs downregulation of mono-ubiquitylated H2A to support spermatocyte gene expression and differentiation.
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作者：
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通讯作者：
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