The Nano Center, Building 206 room B-840, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel, 52900.
Institut für Zytobiologie und Zytopathologie, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35032 Marburg, Germany.
J Cell Sci. 2018 Jun 27;131(12):jcs211433. doi: 10.1242/jcs.211433.
Fe-S clusters act as co-factors of proteins with diverse functions, for example, in DNA repair. Downregulation of the cytosolic iron-sulfur protein assembly (CIA) machinery promotes genomic instability through the inactivation of multiple DNA repair pathways. Furthermore, CIA deficiencies are associated with so far unexplained mitotic defects. Here, we show that CIA2B (also known as FAM96B) and MMS19, constituents of the CIA targeting complex involved in facilitating Fe-S cluster insertion into cytosolic and nuclear target proteins, colocalize with components of the mitotic machinery. Downregulation of CIA2B and MMS19 impairs the mitotic cycle. We identify the chromokinesin KIF4A as a mitotic component involved in these effects. KIF4A binds a Fe-S cluster through its conserved cysteine-rich domain. We demonstrate that this domain is required for the mitosis-related KIF4A localization and for the mitotic defects associated with KIF4A knockout. KIF4A is the first identified mitotic component carrying such a post-translational modification. These findings suggest that the lack of Fe-S clusters in KIF4A upon downregulation of the CIA targeting complex contributes to the mitotic defects.
铁硫簇作为具有多种功能的蛋白质的辅助因子，例如在 DNA 修复中。细胞质铁硫蛋白组装（CIA）机制的下调通过多个 DNA 修复途径的失活促进基因组不稳定性。此外，CIA 缺陷与迄今尚未解释的有丝分裂缺陷有关。在这里，我们表明 CIA2B（也称为 FAM96B）和 MMS19 是参与促进细胞质和核靶蛋白中铁硫簇插入的 CIA 靶向复合物的组成部分，与有丝分裂机制的成分共定位。CIA2B 和 MMS19 的下调会损害有丝分裂周期。我们确定染色质动力蛋白 KIF4A 是参与这些作用的有丝分裂成分。KIF4A 通过其保守的富含半胱氨酸的结构域与铁硫簇结合。我们证明该结构域对于与有丝分裂相关的 KIF4A 定位以及与 KIF4A 敲除相关的有丝分裂缺陷是必需的。KIF4A 是第一个被鉴定为携带这种翻译后修饰的有丝分裂成分。这些发现表明，CIA 靶向复合物下调时 KIF4A 中缺乏铁硫簇会导致有丝分裂缺陷。
