Kdm3a lysine demethylase is an Hsp90 client required for cytoskeletal rearrangements during spermatogenesis.
Kdm3a lysine demethylase is an Hsp90 client required for cytoskeletal rearrangements during spermatogenesis.
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DOI：
10.1091/mbc.e13-08-0471
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发表时间：
2014-04
影响因子：
3.3
通讯作者：
Yeyati PL
中科院分区：
文献类型：
--
作者：
Kasioulis I;Syred HM;Tate P;Finch A;Shaw J;Seawright A;Fuszard M;Botting CH;Shirran S;Adams IR;Jackson IJ;van Heyningen V;Yeyati PL
染色质重塑酶也可以发挥非组蛋白的作用，扩大其生物学功能。研究表明，Kdm3a与细胞质中细胞伴侣的结合与导致酶缺失小鼠不育的形态发生事件有关。这证明Kdm3a不仅仅是一个组蛋白修饰子。赖氨酸去甲基化酶Kdm3a （Jhdm2a, Jmjd1a）通过其在染色质重塑中的核作用，在男性生育、性别决定和代谢稳态中是必需的。许多组蛋白修饰酶具有额外的非组蛋白底物，以及非酶功能，有助于其生物学作用的全谱事件。我们提出了两种Kdm3a小鼠模型，它们表现出细胞质缺陷，这可能部分解释了之前报道的全球精子症表型。电镜显示，Kdm3a去甲基化酶活性不高的小鼠顶体和顶突异常，核尾端没有着床窝，从而影响了精子头伸长所需的细胞质结构。我们描述了一种具有酶活性的新的Kdm3a亚型，并表明Kdm3a的亚细胞分布、蛋白质水平和赖氨酸去甲基化活性依赖于Hsp90。我们发现Kdm3a突变小鼠成熟精细胞的细胞质结构受到影响，进而显示β-肌动蛋白和γ-微管蛋白的分离发生改变。因此，Kdm3a是一种多功能的Hsp90客户蛋白，直接参与细胞骨架成分的调节。
Chromatin remodeling enzymes can also have nonhistone roles, broadening their biological functions. It is shown that Kdm3a binding to cellular chaperones in the cytoplasm is relevant for morphogenetic events leading to infertility in enzymatically null mice. This provides evidence that Kdm3a is not just a histone modifier. The lysine demethylase Kdm3a (Jhdm2a, Jmjd1a) is required for male fertility, sex determination, and metabolic homeostasis through its nuclear role in chromatin remodeling. Many histone-modifying enzymes have additional nonhistone substrates, as well as nonenzymatic functions, contributing to the full spectrum of events underlying their biological roles. We present two Kdm3a mouse models that exhibit cytoplasmic defects that may account in part for the globozoospermia phenotype reported previously. Electron microscopy revealed abnormal acrosome and manchette and the absence of implantation fossa at the caudal end of the nucleus in mice without Kdm3a demethylase activity, which affected cytoplasmic structures required to elongate the sperm head. We describe an enzymatically active new Kdm3a isoform and show that subcellular distribution, protein levels, and lysine demethylation activity of Kdm3a depended on Hsp90. We show that Kdm3a localizes to cytoplasmic structures of maturing spermatids affected in Kdm3a mutant mice, which in turn display altered fractionation of β-actin and γ-tubulin. Kdm3a is therefore a multifunctional Hsp90 client protein that participates directly in the regulation of cytoskeletal components.