Ubiquitin And SUMO Post-Translational Modifications In Development And Disease

泛蛋白样SUMO蛋白的翻译后修饰调节广泛的细胞过程。我们对去小糖基化酶SENP 1的研究首次显示了该途径在发育中的作用，特别是在胎盘的形成和功能中。相扑领域的一个主要问题是如何实现特异性。如何选择特定的靶蛋白进行SUMO化或去SUMO化，以及SUMO 1与SUMO 2或SUMO 3的结合是如何规定的？我们已经表明，缺乏SUMO 1的小鼠是可行的，显然是由于SUMO 2/3的补偿利用SUMO 1靶向的SUMO化。对不同SUMO蛋白的独特和共有功能的进一步了解来自对SENP 1突变体的进一步分析。我们以前的数据表明，观察到的SENP 1表型缺陷是由于更高的稳态水平的结合SUMO 1，而不是SUMO 2或SUMO 3。因此，我们询问在SENP 1突变背景中降低总SUMO 1水平是否会挽救表型。我们已经注意到，SUMO 1突变杂合子小鼠的高分子量SUMO 1结合物水平显著降低。通过与SENP 1突变体杂交，我们产生了SENP 1纯合胚胎，这些胚胎对于SUMO 1突变也是杂合的。发现这些胚胎中SUMO 1缀合物的水平显著降低，接近野生型水平，尽管在这些胚胎中去小泛素化活性仍然受到损害。重要的是，这些胚胎存活到出生，提供了SENP 1发育缺陷依赖于SUMO 1的有力证据。令人惊讶的是，从SENP 1突变体背景中完全消除SUMO 1会导致更严重的表型，突变体甚至在更早的发育阶段死亡。与SUMO 1或SENP 1突变体不同，双纯合胚胎积累了显著水平的SUMO 2/3结合蛋白。这些发现提供了进一步的证据表明，靶蛋白通常与SUMO 1 sumoylated可以进行补偿共轭与SUMO 2/3后，SUMO 1的损失。此外，在另外缺乏SENP 1的情况下，这些SUMO 2/3缀合物的积累可能对发育中的胚胎具有甚至更严重的后果，这可能是由于不适当的SUMO parabolic使用。

Post-translational modification with the ubiquitin-like SUMO proteins regulates a wide range of cellular processes. Our work on the desumoylating enzyme SENP1 was the first to show a role for this pathway in development, specifically in the formation and function of the placenta. A major question in the SUMO field is how is specificity achieved. How are specific target proteins selected for sumoylation or desumoylation and what specifies the conjugation of SUMO1 vs. SUMO2 or SUMO3? We have shown that mice lacking SUMO1 are viable, apparently due to the compensatory utilization of SUMO2/3 for sumoylation of SUMO1 targets. Additional insight into the distinct and shared functions of the different SUMO proteins has come from further analysis of the SENP1 mutant. Our previous data suggested that the observed SENP1 phenotypic defects were due specifically to higher steady state levels of conjugated SUMO1 only, and not SUMO2 or SUMO3. We therefore asked whether reducing total SUMO1 levels in the SENP1 mutant background would rescue the phenotype. We had noted that mice heterozygous for the SUMO1 mutation showed a significant reduction in the level of high molecular mass SUMO1 conjugates. By crossing to the SENP1 mutant we generated SENP1 homozygous embryos that were also heterozygous for the SUMO1 mutation. These were found to have a striking reduction in the level of SUMO1 conjugates, approaching wild-type levels, although desumoylation activity still is compromised in these embryos. Importantly, these embryos survived to birth providing firm evidence that the SENP1 developmental defects are SUMO1 dependent. Surprisingly, completely eliminating SUMO1 from the SENP1 mutant background causes a more severe phenotype, with mutants dying at even earlier developmental stages. Unlike SUMO1 or SENP1 mutants, the double homozygous embryos accumulate significant levels of SUMO2/3 conjugated proteins. These findings provide further evidence that target proteins normally sumoylated with SUMO1 can undergo compensatory conjugation with SUMO2/3 upon the loss of SUMO1. Further, in the additional absence of SENP1, the accumulation of these SUMO2/3 conjugates can have even more severe consequences for the developing embryo perhaps because of inappropriate SUMO paralog usage.