HSF4 regulates DLAD expression and promotes lens de-nucleation
HSF4 regulates DLAD expression and promotes lens de-nucleation
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HSF4 调节 DLAD 表达并促进晶状体脱核。
DOI：
10.1016/j.bbadis.2013.03.007
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发表时间：
2013-08-01
影响因子：
6.2
通讯作者：
Liu, Mugen
中科院分区：
文献类型：
--
作者：
Cui, Xiukun;Wang, Lei;Liu, Mugen
HSF4突变导致先天性和年龄相关性白内障。本研究的目的是探讨HSF 4基因突变导致白内障形成的机制。细胞核DNA的降解是透镜纤维分化所必需的。DNA酶2 β（DLAD）在透镜细胞中高度表达，DLAD基因缺陷的小鼠会发生核性白内障。在本研究中，我们发现HSF 4通过直接结合DIAD启动子促进DIAD的表达和DNA酶活性。相反，HSF4白内障致病突变未能结合DLAD启动子，从而消除了DLAD的表达和DNA酶活性。这些结果通过斑马鱼中的HSF 4敲低得到证实，其导致透镜的不完全脱核以及DLAD的表达和活性降低。总之，我们的研究结果表明，HSF 4发挥其功能透镜分化通过积极调节DIAD的表达和活性，从而促进脱核的透镜纤维细胞。我们证明HSF4白内障致病突变消除了DLAD表达的诱导，揭示了HSF4突变如何导致白内障发生的新分子机制。(C)2013爱思唯尔有限公司版权所有。
HSF4 mutations lead to both congenital and age-related cataract. The purpose of this study was to explore the mechanism of cataract formation caused by HSF4 mutations. The degradation of nuclear DNA is essential for the lens fiber differentiation. DNase 2 beta (DLAD) is highly expressed in lens cells, and mice with deficiencies in the DLAD gene develop nuclear cataracts. In this study, we found that HSF4 promoted the expression and DNase activity of DIAD by directly binding to the DIAD promoter. In contrast, HSF4 cataract causative mutations failed to bind to the DLAD promoter, abrogating the expression and DNase activity of DLAD. These results were confirmed by HSF4 knockdown in zebrafish, which led to incomplete de-nucleation of the lens and decreased expression and activity of DLAD. Together, our results suggest that HSF4 exerts its function on lens differentiation via positive regulation of DIAD expression and activity, thus facilitating de-nucleation of lens fiber cells. Our demonstration that HSF4 cataract causative mutations abrogate the induction of DLAD expression reveals a novel molecular mechanism regarding how HSF4 mutations cause cataractogenesis. (C) 2013 Elsevier B.V. All rights reserved.