Sumoylation differentially regulates Sp1 to control cell differentiation
Sumoylation differentially regulates Sp1 to control cell differentiation
复制标题
Sumoylation 差异调节 Sp1 来控制细胞分化
DOI：
10.1073/pnas.1315034111
复制
发表时间：
2014-04-15
影响因子：
11.1
通讯作者：
Li, David Wan-Cheng
中科院分区：
文献类型：
--
作者：
Gong, Lili;Ji, Wei-Ke;Li, David Wan-Cheng
意义哺乳动物小泛素样修饰物(SUMO)积极参与调节不同细胞类型的分化。然而，SUMO1和SUMO2/3的确切功能还没有定义。在这里，我们第一次证明，据我们所知，SUMO1促进细胞分化，而SUMO2/3抑制细胞分化。从机制上讲，我们证明了特异性蛋白1是SUMO1结合激活的主要靶点，但通过我们新发现的K683残基和已知的K16位点，被SUMO2/3介导的苏莫化抑制。哺乳动物小泛素样修饰物(SUMO)积极参与调节不同细胞类型的分化。然而，相扑亚型之间的功能差异及其作用机制在很大程度上仍不清楚。以眼球晶状体为模型系统，我们证明了不同的相扑在调节上皮细胞向纤维细胞分化的过程中具有不同的功能。在晶状体分化过程中，SUMO1和SUMO2/3表现出不同的表达、定位和靶点，提示其功能不同。事实上，SUMO2/3的过表达，而不是SUMO1，抑制了碱性(B)成纤维细胞生长因子诱导的细胞分化。相反，敲除SUMO1，而不是SUMO2/3，也抑制了bFGF的作用。在机制上，特异性蛋白1(Sp1)是一种主要的转录因子，控制晶状体特异性基因的表达，如β晶体蛋白，受Sumo1正调控，但受Sumo2负调控。SUMO2被发现通过几种机制抑制Sp1的功能：在K683处对其求和以减弱DNA结合，在K16处通过增加其周转来抑制Sp1的功能。SUMO2还干扰Sp1和辅活化子p300之间的相互作用，并招募抑制因子Sp3到β-晶体蛋白基因启动子，以负向调节它们的表达。因此，在晶状体发育过程中，稳定的SUMO1，但减少的SUMO2/3，对于正常的晶状体分化是必要的。为支持这一结论，SUMO1和Sp1在晶状体发育的早期和后期形成了复合体。相反，SUMO2/3和Sp1之间的相互作用仅在晶状体囊泡的初始阶段被检测到。总之，我们的结果确定了不同相扑亚型的不同作用，并首次证明，据我们所知，Sp1是相扑控制细胞分化的主要转录因子靶标。
Significance The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the exact functions of SUMO1 and SUMO2/3 have not been defined. Here, we demonstrate for the first time, to our knowledge, that SUMO1 promotes cell differentiation whereas SUMO2/3 inhibits cell differentiation. Mechanistically, we demonstrate that specificity protein 1 is the major target activated by SUMO1 conjugation but is repressed by SUMO2/3-mediated sumoylation via our newly identified K683 residue, as well as the known K16 site. The mammalian small ubiquitin-like modifiers (SUMOs) are actively involved in regulating differentiation of different cell types. However, the functional differences between SUMO isoforms and their mechanisms of action remain largely unknown. Using the ocular lens as a model system, we demonstrate that different SUMOs display distinct functions in regulating differentiation of epithelial cells into fiber cells. During lens differentiation, SUMO1 and SUMO2/3 displayed different expression, localization, and targets, suggesting differential functions. Indeed, overexpression of SUMO2/3, but not SUMO1, inhibited basic (b) FGF-induced cell differentiation. In contrast, knockdown of SUMO1, but not SUMO2/3, also inhibited bFGF action. Mechanistically, specificity protein 1 (Sp1), a major transcription factor that controls expression of lens-specific genes such as β-crystallins, was positively regulated by SUMO1 but negatively regulated by SUMO2. SUMO2 was found to inhibit Sp1 functions through several mechanisms: sumoylating it at K683 to attenuate DNA binding, and at K16 to increase its turnover. SUMO2 also interfered with the interaction between Sp1 and the coactivator, p300, and recruited a repressor, Sp3 to β-crystallin gene promoters, to negatively regulate their expression. Thus, stable SUMO1, but diminishing SUMO2/3, during lens development is necessary for normal lens differentiation. In support of this conclusion, SUMO1 and Sp1 formed complexes during early and later stages of lens development. In contrast, an interaction between SUMO2/3 and Sp1 was detected only during the initial lens vesicle stage. Together, our results establish distinct roles of different SUMO isoforms and demonstrate for the first time, to our knowledge, that Sp1 acts as a major transcription factor target for SUMO control of cell differentiation.