Abstract
SUMO conjugation has emerged as a dynamic process in regulating protein function. Here we identify estrogen receptor β (ERβ) to be a new target of SUMO-1. ERβ SUMO-1 modification occurs on a unique nonconsensus sumoylation motif which becomes fully competent upon phosphorylation of its contained serine residue, which provides the essential negative charge for sumoylation. This process is further regulated by phosphorylation of additional adjacent serine residues by glycogen synthase kinase 3β (GSK3β), which maximizes ERβ sumoylation in response to hormone. SUMO-1 attachment prevents ERβ degradation by competing with ubiquitin at the same acceptor site and dictates ERβ transcriptional inhibition by altering estrogen-responsive target promoter occupancy and gene expression in breast cancer cells. These findings uncovered a novel phosphorylated sumoylation motif (pSuM), which consists of the sequence ψKXS (where ψ represents a large hydrophobic residue) and which is connected to a GSK3-activated extension that functions as a SUMO enhancer. This extended pSuM offers a valuable signature to predict SUMO substrates under protein kinase regulation.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06624-11.
ACKNOWLEDGMENTS
We thank Dirk Bohmann and Daniel Bailey for the generous gifts of the respective plasmids for ubiquitin and SENP1. We thank Jean St-Louis for advice and members of the A. Tremblay lab for critical reading of the manuscript and useful comments.
N.P. is supported by a doctoral award from the Fonds de la Recherche en Santé du Québec and from the Fondation de l'Hôpital Ste-Justine (FHSJ), S.B. is supported by FHSJ and the Faculté des Études Supérieures et Postdoctorales, and M.S. is supported by FHSJ. A.T. is a new investigator of the Canadian Institutes of Health Research (CIHR). This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada, CIHR, and the Canadian Foundation for Innovation (to A.T.).
We have no competing interests to declare.