Article abstract
Nature Cell Biology 10, 547 - 555 (2008)
Published online: 13 April 2008 | doi:10.1038/ncb1717
Arsenic degrades PML or PML–RAR
through a SUMO-triggered RNF4/ubiquitin-mediated pathway
Valérie Lallemand-Breitenbach1,5, Marion Jeanne1,5, Shirine Benhenda1, Rihab Nasr1, Ming Lei1, Laurent Peres1, Jun Zhou1,2, Jun Zhu1,2, Brian Raught3 & Hugues de Thé1,2,4
Abstract
In acute promyelocytic leukaemia (APL), arsenic trioxide induces degradation of the fusion protein encoded by the PML–RARA oncogene, differentiation of leukaemic cells and produces clinical remissions. SUMOylation of its PML moiety was previously implicated, but the nature of the degradation pathway involved and the role of PML–RAR
catabolism in the response to therapy have both remained elusive. Here, we demonstrate that arsenic-induced PML SUMOylation triggers its Lys 48-linked polyubiquitination and proteasome-dependent degradation. When exposed to arsenic, SUMOylated PML recruits RNF4, the human orthologue of the yeast SUMO-dependent E3 ubiquitin-ligase, as well as ubiquitin and proteasomes onto PML nuclear bodies. Arsenic-induced differentiation is impaired in cells transformed by a non-degradable PML–RAR SUMOylation mutant or in APL cells transduced with a dominant-negative RNF4, directly implicating PML–RAR catabolism in the therapeutic response. We thus identify PML as the first protein degraded by SUMO-dependent polyubiquitination. As PML SUMOylation recruits not only RNF4, ubiquitin and proteasomes, but also many SUMOylated proteins onto PML nuclear bodies, these domains could physically integrate the SUMOylation, ubiquitination and degradation pathways.
- Université de Paris 7/CNRS UMR 7151, Equipe Labellisée N°11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, 1, Av. C. Vellefaux 75475 Paris CEDEX 10 France.
- CNRS Laboratoire Associé MPC, Shanghai Institute of Hematology, Rui Jin Hospital, 197 Rui Jin Road, 200025 Shanghai China.
- Ontario Cancer Institute and McLaughlin Centre for Molecular Medicine 101 College St., MaRS TMDT 9-805, Toronto, ON M5G 1L7 Canada.
- Institut Universitaire de France.
- These authors contributed equally to this work.
Correspondence to: Hugues de Thé1,2,4 e-mail: dethe@univ-paris-diderot.fr
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