Journal
NATURE CELL BIOLOGY
Volume 10, Issue 5, Pages 538-546Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1716
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- Cancer Research UK Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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In acute promyelocytic leukaemia (APL), the promyelocytic leukaemia (PML) protein is fused to the retinoic acid receptor a (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.
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