SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation
SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation
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DOI：
10.1074/jbc.m301344200
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发表时间：
2003-08-08
影响因子：
4.8
通讯作者：
Matunis, MJ
中科院分区：
文献类型：
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作者：
Rogers, RS;Horvath, CM;Matunis, MJ
PIAS（活化STAT蛋白抑制剂）蛋白家族是作为活化信号转导和转录激活因子（STATs）的抑制剂首次被发现的。最近，这些蛋白被证明可以作为E3连接酶，促进一些转录调节因子的SUMO修饰。我们已经研究了PIAS蛋白对STAT1转录活性的影响与PIAS蛋白作为SUMO E3连接酶的能力之间的关系。我们证明STAT1是SUMO修饰的底物，piasx - α而不是PIAS1作为E3连接酶促进STAT1修饰。此外，我们还绘制了STAT1上SUMO修饰的主要位点为赖氨酸703。这个赖氨酸残基与位置701的调节性酪氨酸残基非常接近，其磷酸化介导STAT1激活以响应细胞因子信号。在体外和体内，赖氨酸703突变为精氨酸可消除STAT1的SUMO修饰。然而，这种突变不影响STAT1的激活，也不影响PIAS1或piasx - α作为STAT1介导的转录激活抑制剂的能力。我们的研究结果表明，PIAS蛋白对STAT1的抑制不需要对STAT1本身进行SUMO修饰。然而，考虑到SUMO修饰位点与酪氨酸701之间的距离很近，STAT1的SUMO修饰可能在功能上很重要。
The PIAS (protein inhibitors of activated STAT) family of proteins were first discovered as inhibitors of activated signal transducers and activators of transcription (STATs). More recently these proteins have been shown to function as E3 ligases that promote the SUMO modification of a number of transcription regulators. We have investigated the relationship between the effects of PIAS proteins on STAT1 transcriptional activity and the ability of the PIAS proteins to function as SUMO E3 ligases. We demonstrate that STAT1 is a substrate for SUMO modification and that PIASx-alpha, but not PIAS1, functions as an E3 ligase to promote STAT1 modification. In addition, we have mapped the major site for SUMO modification on STAT1 to lysine 703. This lysine residue is in close proximity to the regulatory tyrosine residue at position 701, whose phosphorylation mediates STAT1 activation in response to cytokine signaling. Mutation of lysine 703 to arginine abolishes SUMO modification of STAT1 both in vitro and in vivo. However, this mutation does not affect the activation of STAT1 or the ability of either PIAS1 or PIASx-alpha to function as an inhibitor of STAT1-mediated transcription activation. Our findings demonstrate that inhibition of STAT1 by PIAS proteins does not require SUMO modification of STAT1 itself. SUMO modification of STAT1 may nonetheless be functionally important given the close proximity between the SUMO modification site and tyrosine 701.