Acetylation of SUMO paralogs as a determinant of SUMO-mediated protein networks

SUMO 旁系同源物的乙酰化作为 SUMO 介导的蛋白质网络的决定因素

• 批准号: 242915414
• 负责人: Professor Dr. Stefan Müller
• 金额: --
• 依托单位: Institut für Biochemie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242915414?language=en
• 关键词: Acetylation; SUMO; paralogs; determinant; mediated

The post-translational modification (PTM) of proteins through phosphorylation, acetylation or ubiquitylation is a central mechanism for the control of cellular signalling networks. A general principle is the selective recognition of the modified protein by a specific interaction domain. Modification by the ubiquitin-related SUMO protein also modulates specific protein-protein interactions thereby regulating various cellular signalling processes. Attachment of SUMO typically earmarks a protein for the recognition by a binding partner that contains a SUMO interaction motif (SIM). Prominent examples are the targeting of sumoylated RanGAP1 to RanBP2 or the SUMO/SIM-dependent assembly of PML nuclear bodies (NBs). Canonical SIMs are characterized by a stretch of hydrophobic residues, which interacts with a hydrophobic pocket on the surface of SUMO. In a subset of SIM modules acidic residues flank the hydrophobic core and enhance the binding to SUMO via electrostatic interactions with a basic interface on the modifier. Despite these relatively detailed molecular insights in SUMO/SIM interactions it is unclear how specificity and dynamics of these interactions are regulated. We recently unravelled the importance of PTMs for this process. We initially found that in a subset of SIM-containing proteins serine or threonine residues that juxtapose the hydrophobic region are phosphorylated. The additional negative charges of phosphorylated residues in these phosphoSIMs enhance the binding to the basic interface of SUMO. Very recently we defined site-specific acetylation of lysine residues within this basic interface as a novel regulatory principle in the control of SUMO/SIM interactions. We could show that acetylation of SUMO1 at K37 or SUMO2 at K33 still allows binding to RanBP2, but precludes the interaction with PIAS family members, PML or Daxx. Accordingly, SUMO affected the assembly of PML NBs and in particular prevented the SIM-dependent recruitment of the co-repressor Daxx to these structures. Importantly, in biochemical experiments we could further demonstrate that K33 acetylated SUMO2 serves as a binding platform for the Bromodomain (BRD) containing protein p300. In this proposal we aim to delineate how acetylation controls SUMO-mediated protein networks. We aim to identify specific substrates that are regulated by acetyl-SUMO modification and seek to get insight how this affects selected cellular pathways, in particular the control of gene expression. Finally, we want to unravel how the acetylation of SUMO is regulated.Within the funding period we anticipate to reach the following milestones:1. Decipher a specific acetyl-code on SUMO paralogs that determines the selectivity of SUMO/SIM and acetyl-SUMO/BRD interactions.2. Define targets of the acetyl-SUMO-code and delineate its impact on gene expression.3. Identify the regulatory components and physiological stimuli that control acetylation of SUMO paralogs.

通过磷酸化、乙酰化或泛素化进行的蛋白质翻译后修饰 (PTM) 是控制细胞信号网络的核心机制。一般原则是通过特定的相互作用结构域选择性识别修饰的蛋白质。泛素相关 SUMO 蛋白的修饰还可调节特定的蛋白质-蛋白质相互作用，从而调节各种细胞信号传导过程。 SUMO 的附着通常会标记蛋白质，以供包含 SUMO 相互作用基序 (SIM) 的结合配偶体识别。突出的例子是将 sumoylated RanGAP1 靶向 RanBP2 或 PML 核体 (NB) 的 SUMO/SIM 依赖性组装。规范 SIM 的特征是一段疏水残基，它与 SUMO 表面的疏水口袋相互作用。在 SIM 模块的子集中，酸性残基位于疏水核心的侧翼，并通过与改性剂上的碱性界面的静电相互作用增强与 SUMO 的结合。尽管对 SUMO/SIM 相互作用有这些相对详细的分子见解，但尚不清楚这些相互作用的特异性和动力学是如何调节的。我们最近揭示了 PTM 在此过程中的重要性。我们最初发现，在含有 SIM 的蛋白质子集中，与疏水区域并列的丝氨酸或苏氨酸残基被磷酸化。这些 phosphSIM 中磷酸化残基的额外负电荷增强了与 SUMO 基本界面的结合。最近，我们将这个基本界面内赖氨酸残基的位点特异性乙酰化定义为控制 SUMO/SIM 相互作用的新调控原理。我们可以证明 SUMO1 在 K37 处或 SUMO2 在 K33 处的乙酰化仍然允许与 RanBP2 结合，但排除与 PIAS 家族成员、PML 或 Daxx 的相互作用。因此，SUMO 影响了 PML NB 的组装，特别是阻止了辅助阻遏物 Daxx 依赖 SIM 募集到这些结构中。重要的是，在生化实验中，我们可以进一步证明 K33 乙酰化 SUMO2 可作为含有蛋白质 p300 的布罗莫结构域 (BRD) 的结合平台。在本提案中，我们的目标是描述乙酰化如何控制 SUMO 介导的蛋白质网络。我们的目标是识别受乙酰基相扑修饰调节的特定底物，并寻求了解其如何影响选定的细胞途径，特别是基因表达的控制。 最后，我们想要阐明 SUMO 的乙酰化是如何调控的。在资助期内，我们预计将达到以下里程碑：1。 破译SUMO旁系同源物上的特定乙酰基代码，该代码决定SUMO/SIM和乙酰基-SUMO/BRD相互作用的选择性。2． 定义乙酰基-SUMO 代码的目标并描述其对基因表达的影响。3． 确定控制 SUMO 旁系同源物乙酰化的调节成分和生理刺激。

项目成果

Acetylation of SUMO2 at lysine 11 favors the formation of non‐canonical SUMO chains

SUMO2 在赖氨酸 11 处的乙酰化有利于非经典 SUMO 链的形成

• DOI: 10.15252/embr.201846117
• 发表时间: 2018-09-10
• 期刊: EMBO reports
• 影响因子: 7.7
• 作者: Anne Gärtner;K. Wagner;Soraya Hölper;K. Kunz;Manuel S. Rodríguez;S. Müller
• 通讯作者: S. Müller

The SUMO-specific isopeptidase SENP3 regulates MLL1/MLL2 methyltransferase complexes and controls osteogenic differentiation.

SUMO 特异性肽酶 SENP3 调节 MLL1/MLL2 甲基转移酶复合物并控制成骨分化。

• DOI: 10.1016/j.molcel.2014.05.011
• 发表时间: 2014-07-03
• 期刊: Molecular cell
• 影响因子: 16
• 作者: A. Nayak;S. Viale;C. Morsczeck;S. Muller
• 通讯作者: S. Muller

The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics.

SUMO 异肽酶 SENP6 在基因组维护和染色体动力学中充当染色质驻留变阻器。

• DOI: 10.1016/j.celrep.2019.08.106
• 发表时间: 2019-10-08
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: K. Wagner;K. Kunz;Tanja Piller;G. Tascher;Soraya Hölper;Per Stehmeier;Jan Keiten;M. Schick;U. Keller;S. Müller
• 通讯作者: S. Müller

The AAA ATPase MDN1 Acts as a SUMO-Targeted Regulator in Mammalian Pre-ribosome Remodeling.

AAA ATPase MDN1 在哺乳动物前核糖体重塑中充当 SUMO 靶向调节剂。

• DOI: 10.1016/j.molcel.2016.09.039
• 发表时间: 2016-11-03
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Nithya Raman;E. Weir;S. Müller
• 通讯作者: S. Müller

Site-specific inhibition of the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 selectively impairs SUMO chain formation

位点特异性抑制小泛素样修饰剂 (SUMO) 结合酶 Ubc9 选择性损害 SUMO 链形成

• DOI: 10.1074/jbc.m117.794255
• 发表时间: 2017-08-07
• 期刊: The Journal of Biological Chemistry
• 作者: S. Wiechmann;Anne Gärtner;Andreas Kniss;A. Stengl;C. Behrends;V. Rogov;Manuel S. Rodríguez;V. Dötsch;S. Müller;A. Ernst
• 通讯作者: A. Ernst