Tatham Michael H, Geoffroy Marie-Claude, Shen Linnan, Plechanovova Anna, Hattersley Neil, Jaffray Ellis G, Palvimo Jorma J, Hay Ronald T
Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13.
In acute promyelocytic leukaemia (APL), the promyelocytic leukaemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). This disease can be treated effectively with arsenic, which induces PML modification by small ubiquitin-like modifiers (SUMO) and proteasomal degradation. Here we demonstrate that the RING-domain-containing ubiquitin E3 ligase, RNF4 (also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. RNF4 depletion or proteasome inhibition led to accumulation of mixed, polyubiquitinated, poly-SUMO chains. PML protein accumulated in RNF4-depleted cells and was ubiquitinated by RNF4 in a SUMO-dependent fashion in vitro. In the absence of RNF4, arsenic failed to induce degradation of PML and SUMO-modified PML accumulated in the nucleus. These results demonstrate that poly-SUMO chains can act as discrete signals from mono-SUMOylation, in this case targeting a poly-SUMOylated substrate for ubiquitin-mediated proteolysis.
在急性早幼粒细胞白血病（APL）中，早幼粒细胞白血病（PML）蛋白与维甲酸受体α（RAR）融合。这种疾病可用砷有效治疗，砷可通过小泛素样修饰物（SUMO）诱导PML修饰并经蛋白酶体降解。在此，我们证明含RING结构域的泛素E3连接酶RNF4（也称为SNURF）靶向多聚SUMO修饰的蛋白以进行泛素介导的降解。RNF4缺失或蛋白酶体抑制导致混合的、多聚泛素化的、多聚SUMO链的积累。PML蛋白在RNF4缺失的细胞中积累，并且在体外RNF4以SUMO依赖的方式使其泛素化。在缺乏RNF4的情况下，砷未能诱导PML降解，且SUMO修饰的PML在细胞核中积累。这些结果表明，多聚SUMO链可作为与单SUMO化不同的信号，在这种情况下，将多聚SUMO化底物靶向泛素介导的蛋白水解。
