DataSheet1_FBXO38 Ubiquitin Ligase Controls Centromere Integrity via ZXDA/B Stability.pdf

Alterations in the gene encoding the E3 ubiquitin ligase substrate receptor FBXO38 have been associated with several diseases, including early-onset motor neuronopathy. However, the cellular processes affected by the enzymatic action of FBXO38 are not yet known. Here, we identify the zinc finger proteins ZXDA/B as its interaction partners. FBXO38 controls the stability of ZXDA/B proteins via ubiquitination and proteasome-dependent degradation. We show that ZXDA/B proteins associate with the centromeric protein CENP-B and that the interaction between ZXDA/B and FBXO38 or CENP-B is mutually exclusive. Functionally, ZXDA/B factors control the protein level of chromatin-associated CENP-B. Furthermore, their inappropriate stabilization leads to upregulation of CENP-A and CENP-B positive centromeric chromatin. Thus we demonstrate a previously unknown role of cullin-dependent protein degradation in the control of centromeric chromatin integrity.

编码E3泛素连接酶底物受体FBXO38的基因突变与多种疾病，包括早发型运动神经元病相关。然而，FBXO38酶促作用所影响的细胞过程尚不明确。本研究中，我们鉴定出锌指蛋白ZXDA/B为其相互作用伙伴。FBXO38通过泛素化和蛋白酶体依赖性降解调控ZXDA/B蛋白的稳定性。研究结果表明，ZXDA/B蛋白与着丝粒蛋白CENP-B相结合，且ZXDA/B与FBXO38或CENP-B之间的相互作用是互斥的。在功能上，ZXDA/B因子调控与染色质相关的CENP-B蛋白水平。此外，其不适当的稳定化导致CENP-A和CENP-B阳性着丝粒染色质的上调。因此，本研究揭示了cullin依赖性蛋白降解在控制着丝粒染色质完整性中的先前未知作用。