Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier
Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier
复制标题
DOI：
10.1074/jbc.m709748200
复制
发表时间：
2008-08-22
影响因子：
4.8
通讯作者：
Schwartz, Robert J.
中科院分区：
文献类型：
--
作者：
Wang, Jun;Zhang, Hua;Schwartz, Robert J.
心脏特异的同源异型盒基因NKX2.5是NK-2类家族的成员，在心脏发生中起核心作用，是小泛素样修饰物(SUMO)的靶标。NKX2.5的第51个氨基酸被相扑修饰，这是一种跨物种保守的赖氨酸残基，但在其他NK-2成员中不存在。这种赖氨酸转化为精氨酸(K51R)大大减少了NKX2.5与DNA的结合，也降低了其转录活性。没想到，突变体K51R成为泛素的靶点。E3连接酶PIAS蛋白PIAS1、PIASx和PIASy，而不是PIAS3，增强了相扑-1与NKX2.5在主要相扑受体位点上的结合。SUMO-2与NKX2.5的连接仅由PIASx催化，其他PIAS蛋白不催化。相扑结合稳定了含有NKX2.5的复合体的形成，从而导致了强劲的转录激活。因此，相扑修饰对NKX2.5转录活性具有正向调节作用。
The cardiac specific homeobox gene nkx2.5, a member of the nk-2 class family, plays a central role in cardiogenesis and is a target of the small ubiquitin-like modifier (SUMO). Nkx2.5 was modified by SUMO on its 51st amino acid, a lysine residue conserved across species but absent in other nk-2 members. Conversion of this lysine to an arginine (K51R) substantially reduced Nkx2.5 DNA binding and also its transcriptional activity. Unexpectedly, mutant K51R was targeted by ubiquitin. E3 ligase PIAS proteins PIAS1, PIASx, and PIASy, but not PIAS3, enhanced SUMO-1 attachment to Nkx2.5 on the primary SUMO acceptor site. SUMO-2 linkage to Nkx2.5 was catalyzed only by PIASx and not by other PIAS proteins. SUMO conjugation stabilized the formation of Nkx2.5-containing complexes that led to robust transcriptional activation. Thus, SUMO modification serves as a positive regulator for Nkx2.5 transcriptional activity.