SUMOylation modulates the transcription repressor function of RIP140.
RIP140/NRIP1 (receptor-interacting protein 140) functions as a corepressor of nuclear receptors. It plays an important role in the transcriptional control of energy metabolism and female fertility. RIP140 contains four distinct repression domains (RD1-RD4), and the repressive activity of RIP140 involves complex mechanisms. The function of both RD1 and RD2 is linked to recruitment of histone deacetylases and C-terminal binding protein, respectively, but the mechanism of repression for RD3 and RD4 has remained elusive. Because covalent modification by small ubiquitin-like modifiers (SUMO-1, -2, and -3; SUMOylation) is often associated with transcriptional repression, we studied whether SUMOylation is involved in the repressive activity of RIP140. We show that two conserved lysines, Lys(756) and Lys(1154), located in RD3 and RD4, respectively, are subject to reversible SUMOylation, with SUMO-1 being more efficiently conjugated than SUMO-2. Interestingly, mutations of the RIP140 SUMOylation sites compromised the transcription repressor function of RIP140 and blunted its capacity to repress estrogen receptor alpha-dependent transcription. Conjugation of SUMO-1 also influenced the subnuclear distribution pattern of RIP140. In sum, our demonstration that the function of RIP140 repression domains 3 and 4 can be modulated by reversible SUMO modification thus adds a novel level to the regulation of RIP140 activity, which may have ramifications in the control of gene networks exerted by RIP140.
Rytinki
Miia M
MM
Institute of Biomedicine/Medical Biochemistry, University of Kuopio, FI-70211 Kuopio, Finland.
Palvimo
Jorma J
JJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D000078723:Nuclear Receptor Interacting Protein 1; D025842:SUMO-1 Protein / Q000378:metabolism*; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human