Abstract
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.
Highlights
Nurr1 (NR4A2) is a transcription factor with several functions, but highlights for its key role inducing and maintaining midbrain dopamine neurons of the mammalian central nervous system [1]
To further confirm that Nurr1 is a target of small ubiquitin-like modifier (SUMO)-2, we carried out coimmunoprecipitation assays
These results indicate that Nurr1 is a target of SUMO-2 posttranslational modification
Summary
Nurr (NR4A2) is a transcription factor with several functions, but highlights for its key role inducing and maintaining midbrain dopamine neurons of the mammalian central nervous system [1]. Nurr together with Nur (NR4A1, NGFI-B) and Nor (NR4A3) conform the NR4A group of the nuclear receptor superfamily [2]. Nurr shares with the other NR4A members a highly conserved structural organization. This structure consists of an almost identical DNA-binding domain (DBD); a moderately conserved C-terminal region, which encloses both the ligand-binding domain (LBD) and the transcriptional activation function-2 (AF-2); and the N-terminal region containing the AF-1, which is the most divergent domain [3]. Structural studies have shown that the LBD domain of Nurr lacks the cavity to accommodate a ligand, and its AF-2 adopts naturally a stable transcriptional active conformation [4]. Since Nurr is not regulated by endogenous ligands, post-translational modifications are one of the most significant mechanisms to regulate Nurr transcriptional activity
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