RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation

Michael H. Tatham, Marie-Claude Geoffroy, Linnan Shen, Anna Plechanovova, Neil Hattersley, Ellis G. Jaffray, Jorma J. Palvimo, Ronald T. Hay (Lead / Corresponding author)

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    Abstract

    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.

    Original languageEnglish
    Pages (from-to)538-546
    Number of pages9
    JournalNature Cell Biology
    Volume10
    Issue number5
    DOIs
    Publication statusPublished - May 2008

    Keywords

    • ACUTE PROMYELOCYTIC LEUKEMIA
    • NUCLEAR-BODIES
    • DNA-REPAIR
    • SNURF RNF4
    • PROTEINS
    • IDENTIFICATION
    • APOPTOSIS
    • TRIOXIDE
    • COREGULATOR
    • CELLS

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