Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Cell Death Dis. 2012 Sep 27;3(9):e393. doi: 10.1038/cddis.2012.135.
The crucial function of the PTEN tumor suppressor in multiple cellular processes suggests that its activity must be tightly controlled. Both, membrane association and a variety of post-translational modifications, such as acetylation, phosphorylation, and mono- and polyubiquitination, have been reported to regulate PTEN activity. Here, we demonstrated that PTEN is also post-translationally modified by the small ubiquitin-like proteins, small ubiquitin-related modifier 1 (SUMO1) and SUMO2. We identified lysine residue 266 and the major monoubiquitination site 289, both located within the C2 domain required for PTEN membrane association, as SUMO acceptors in PTEN. We demonstrated the existence of a crosstalk between PTEN SUMOylation and ubiquitination, with PTEN-SUMO1 showing a reduced capacity to form covalent interactions with monoubiquitin and accumulation of PTEN-SUMO2 conjugates after inhibition of the proteasome. Moreover, we found that virus infection induces PTEN SUMOylation and favors PTEN localization at the cell membrane. Finally, we demonstrated that SUMOylation contributes to the control of virus infection by PTEN.
PTEN 肿瘤抑制剂在多种细胞过程中发挥着关键作用，这表明其活性必须受到严格控制。膜结合和多种翻译后修饰，如乙酰化、磷酸化、单泛素化和多泛素化，已被报道可调节 PTEN 的活性。在这里，我们证明了 PTEN 还可被小泛素样蛋白，小泛素相关修饰物 1（SUMO1）和 SUMO2 进行翻译后修饰。我们鉴定了赖氨酸残基 266 和主要的单泛素化位点 289，它们都位于 C2 结构域内，对于 PTEN 的膜结合是必需的，是 PTEN 的 SUMO 接受体。我们证明了 PTEN SUMO 化和泛素化之间存在串扰，PTEN-SUMO1 与单泛素形成共价相互作用的能力降低，并且蛋白酶体抑制剂处理后 PTEN-SUMO2 缀合物的积累增加。此外，我们发现病毒感染可诱导 PTEN SUMO 化，并有利于 PTEN 定位于细胞膜。最后，我们证明了 SUMO 化有助于 PTEN 控制病毒感染。
