Prudden John, Pebernard Stephanie, Raffa Grazia, Slavin Daniela A, Perry J Jefferson P, Tainer John A, McGowan Clare H, Boddy Michael N
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
EMBO J. 2007 Sep 19;26(18):4089-101. doi: 10.1038/sj.emboj.7601838. Epub 2007 Aug 30.
We identify the SUMO-Targeted Ubiquitin Ligase (STUbL) family of proteins and propose that STUbLs selectively ubiquitinate sumoylated proteins and proteins that contain SUMO-like domains (SLDs). STUbL recruitment to sumoylated/SLD proteins is mediated by tandem SUMO interaction motifs (SIMs) within the STUbLs N-terminus. STUbL-mediated ubiquitination maintains sumoylation pathway homeostasis by promoting target protein desumoylation and/or degradation. Thus, STUbLs establish a novel mode of communication between the sumoylation and ubiquitination pathways. STUbLs are evolutionarily conserved and include: Schizosaccharomyces pombe Slx8-Rfp (founding member), Homo sapiens RNF4, Dictyostelium discoideum MIP1 and Saccharomyces cerevisiae Slx5-Slx8. Cells lacking Slx8-Rfp accumulate sumoylated proteins, display genomic instability, and are hypersensitive to genotoxic stress. These phenotypes are suppressed by deletion of the major SUMO ligase Pli1, demonstrating the specificity of STUbLs as regulators of sumoylated proteins. Notably, human RNF4 expression restores SUMO pathway homeostasis in fission yeast lacking Slx8-Rfp, underscoring the evolutionary functional conservation of STUbLs. The DNA repair factor Rad60 and its human homolog NIP45, which contain SLDs, are candidate STUbL targets. Consistently, Rad60 and Slx8-Rfp mutants have similar DNA repair defects.
我们鉴定了靶向小泛素样修饰蛋白（SUMO）的泛素连接酶（STUbL）蛋白家族，并提出STUbL可选择性地将小泛素样修饰（sumoylated）蛋白和含有类SUMO结构域（SLD）的蛋白泛素化。STUbL被招募至小泛素样修饰/SLD蛋白是由STUbL N端的串联SUMO相互作用基序（SIM）介导的。STUbL介导的泛素化通过促进靶蛋白去小泛素样修饰和/或降解来维持小泛素样修饰途径的稳态。因此，STUbL在小泛素样修饰和泛素化途径之间建立了一种新的通讯模式。STUbL在进化上是保守的，包括：粟酒裂殖酵母的Slx8-Rfp（创始成员）、智人的RNF4、盘基网柄菌的MIP1和酿酒酵母的Slx5-Slx8。缺乏Slx8-Rfp的细胞会积累小泛素样修饰蛋白，表现出基因组不稳定，并对基因毒性应激高度敏感。这些表型可通过缺失主要的SUMO连接酶Pli1来抑制，这证明了STUbL作为小泛素样修饰蛋白调节剂的特异性。值得注意的是，人类RNF4的表达可恢复缺乏Slx8-Rfp的裂殖酵母中的SUMO途径稳态，强调了STUbL在进化上的功能保守性。含有SLD的DNA修复因子Rad60及其人类同源物NIP45是STUbL的候选靶标。一致地，Rad60和Slx8-Rfp突变体具有相似的DNA修复缺陷。
