Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model
Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model
复制标题
Lamin A 缓冲 CK2 激酶活性以调节早衰小鼠模型的衰老。
DOI：
10.1126/sciadv.aav5078
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发表时间：
2019-03-01
期刊：
影响因子：
13.6
通讯作者：
Wang, Zimei
中科院分区：
文献类型：
--
作者：
Ao, Ying;Zhang, Jie;Wang, Zimei
导致早衰症的核纤层蛋白A突变抑制CK2酶活性，加速实验室小鼠的衰老。核纤层蛋白A缺陷与过早衰老有关。酪蛋白激酶2（CK2）结合核纤层，并且抑制CK2活性诱导癌细胞中的细胞衰老。因此，核纤层蛋白A和CK2可能在老化过程中协同作用。核CK2定位依赖于核纤层蛋白A，核纤层蛋白A羧基末端与CK2α催化核心物理相互作用并抑制其激酶活性。Lmna敲除小鼠胚胎成纤维细胞（MEF）中层蛋白A的缺失会导致CK 2活性增加。相反，在Zmpste24缺陷的MEFs中积累的前层蛋白A表现出高CK2α结合亲和力，并伴随着降低CK2激酶活性。Permidine处理通过释放核纤层蛋白A和CK2之间的相互作用激活CK2，促进DNA损伤修复并改善早衰样特征。这些数据揭示了核纤层蛋白A的一个以前未鉴定的功能，并强调了CK2在调节衰老和老化中的重要作用。
The causative progeria lamin A mutation inhibits CK2 enzyme activity to accelerate aging in laboratory mice. Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A in Lmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates in Zmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.