Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity
Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity
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DOI：
10.1073/pnas.052559499
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发表时间：
2002-03-05
影响因子：
11.1
通讯作者：
Müller, S
中科院分区：
文献类型：
--
作者：
Schmidt, D;Müller, S
p53肿瘤抑制蛋白和c-Jun原癌基因的活性受翻译后修饰（如磷酸化或泛素化）的调节。此外，泛素样修饰物SUMO的共价附着似乎调节了它们的转录活性。泛素化通过与泛素化机制类似的酶途径进行，但需要不同的el激活酶和Ubc9（一种sumo特异性e2偶联酶）。在这里，我们发现PIAS家族的两个成员，PIAS1和PIASxbeta，作为特异性的e3样连接酶，在体外和体内促进p53和c-Jun的summoylation。PIAS蛋白与p53和c-Jun相互作用。此外，它们与Ubc9结合，表明它们将E2酶募集到各自的底物上。SUMO连接酶的活性需要保守的锌指结构域，这与在泛素连接酶的一个子集中发现的必要的RING-finger motif有远亲关系。此外，与ring型泛素连接酶类似，PIASxbeta可以催化自身修饰。因此，这些数据进一步扩展了泛素和SUMO途径之间的相似性。引人注目的是，PIAS蛋白强烈抑制p53的转录活性，这表明PIAS- sumo通路在p53和其他转录因子的调控中起着至关重要的作用。
The activity of the p53 tumor suppressor protein and the c-Jun protooncogene is regulated by posttranslational modifications, such as phosphorylation or ubiquitination. In addition, covalent attachment of the ubiquitin-like modifier SUMO appears to modulate their transcriptional activity. Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different El-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme. Here, we show that two members of the PIAS family, PIAS1 and PIASxbeta, act as specific E3-like ligases that promote sumoylation of p53 and c-Jun in vitro and in vivo. The PIAS proteins physically interact with both p53 and c-Jun. In addition, they bind to Ubc9, suggesting that they recruit the E2 enzyme to their respective substrate. The SUMO ligase activity requires the conserved zinc-finger domain, which is distantly related to the essential RING-finger motif, found in a subset of ubiquitin ligases. Furthermore, similar to RING-type ubiquitin ligases, PIASxbeta can catalyze its own modification. Hence, these data further extend the analogy between the ubiquitin and SUMO pathway. Strikingly, PIAS proteins strongly repress the transcriptional activity of p53, suggesting that the PIAS-SUMO pathway plays a crucial role in the regulation of p53 and presumably other transcription factors.