PIASγ enhanced SUMO-2 modification of Nurr1 activation-function-1 domain limits Nurr1 transcriptional synergy.
PIASγ enhanced SUMO-2 modification of Nurr1 activation-function-1 domain limits Nurr1 transcriptional synergy.
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DOI：
10.1371/journal.pone.0055035
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Andrés ME
中科院分区：
文献类型：
--
作者：
Arredondo C;Orellana M;Vecchiola A;Pereira LA;Galdames L;Andrés ME
Nurr 1（NR 4A 2）是一种转录因子，属于核受体超家族的孤儿NR 4A组。Nurr 1在中脑多巴胺神经元的起源和维持以及外周炎症过程中起关键作用。皮亚斯γ是一种SUMO-E3连接酶，抑制Nurr 1的转录活性。我们报告说，SUMO-2在位于Nurr 1的转录激活功能1域的赖氨酸91 SUMO化Nurr 1。过表达野生型皮亚斯γ可显著促进SUMO-2对Nurr 1的SUMO化，但缺失第一个LXXLL基序的皮亚斯γ突变体（皮亚斯γ mut 1）则不能促进SUMO-2对Nurr 1的SUMO化。该皮亚斯γ mut 1也不能与Nurr 1相互作用并抑制Nurr 1的转录活性。有趣的是，缺失SUMO连接酶活性的突变体皮亚斯γ C342 A仍然能够显著抑制Nurr 1依赖的转录活性，但不能增强Nurr 1的SUMO化。SUMO化缺陷型Nurr 1突变体仅在含有一个以上Nurr 1应答元件的启动子中显示出比野生型Nurr 1更高的转录活性。此外，赖氨酸91，Nurr 1 SUMO化的主要目标是包含在一个典型的协同控制基序，表明SUMO-2翻译后修饰的Nurr 1调节其在复杂的启动子的转录协同作用。总之，皮亚斯γ对Nurr 1有两种负调节作用。一方面，皮亚斯γ通过SUMO化赖氨酸91限制了复合启动子中Nurr 1的反式激活。另一方面，皮亚斯γ通过直接相互作用完全抑制Nurr 1的反式激活，而与其E3连接酶活性无关。
Nurr1 (NR4A2) is a transcription factor that belongs to the orphan NR4A group of the nuclear receptor superfamily. Nurr1 plays key roles in the origin and maintenance of midbrain dopamine neurons, and peripheral inflammatory processes. PIASγ, a SUMO-E3 ligase, represses Nurr1 transcriptional activity. We report that Nurr1 is SUMOylated by SUMO-2 in the lysine 91 located in the transcriptional activation function 1 domain of Nurr1. Nurr1 SUMOylation by SUMO-2 is markedly facilitated by overexpressing wild type PIASγ, but not by a mutant form of PIASγ lacking its first LXXLL motif (PIASγmut1). This PIASγmut1 is also unable to interact with Nurr1 and to repress Nurr1 transcriptional activity. Interestingly, the mutant PIASγC342A that lacks SUMO ligase activity is still able to significantly repress Nurr1-dependent transcriptional activity, but not to enhance Nurr1 SUMOylation. A SUMOylation-deficient Nurr1 mutant displays higher transcriptional activity than the wild type Nurr1 only in promoters harboring more than one Nurr1 response element. Furthermore, lysine 91, the major target of Nurr1 SUMOylation is contained in a canonical synergy control motif, indicating that SUMO-2 posttranslational modification of Nurr1 regulates its transcriptional synergy in complex promoters. In conclusion, PIASγ can exert two types of negative regulations over Nurr1. On one hand, PIASγ limits Nurr1 transactivation in complex promoters by SUMOylating its lysine 91. On the other hand, PIASγ fully represses Nurr1 transactivation through a direct interaction, independently of its E3-ligase activity.
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DOI：
10.1073/pnas.2136933100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Holmstrom, S;Van Antwerp, ME;Iñiguez-Lluhí, JA
通讯作者：
Iñiguez-Lluhí, JA
影响因子：
16
作者：
Gomez, Andrea V.;Galleguillos, Danny;Andres, Maria Estela
通讯作者：
Andres, Maria Estela
影响因子：
5.2
作者：
Jo, A-Young;Kim, Mi-Young;Lee, Hyun-Seob;Rhee, Yong-Hee;Lee, Jeong-Eun;Baek, Kwang-Hyun;Park, Chang-Hwan;Koh, Hyun-Chul;Shin, Incheol;Lee, Yong-Sung;Lee, Sang-Hun
通讯作者：
Lee, Sang-Hun
影响因子：
3.7
作者：
Georges A;Benayoun BA;Marongiu M;Dipietromaria A;L'Hôte D;Todeschini AL;Auer J;Crisponi L;Veitia RA
通讯作者：
Veitia RA
影响因子：
--
作者：
Holmstrom, Sam R.;Chupreta, Sergey;Iniguez-Lluhi, Jorge A.
通讯作者：
Iniguez-Lluhi, Jorge A.