Transcription SUMO System in Full

The SUMO and ubiquitin conjugation systems appear quite similar, although an E3-like protein, which confers target specificity for the latter, has not yet been identified for the former. Sachdev et al. propose that the protein inhibitor of activated STAT (PIAS) functions as a SUMO E3 ligase for lymphoid enhancer factor 1 (LEF1), a transcription factor that is a nuclear mediator of Wnt signaling. PIAS proteins have diverse effects on transcription, both augmenting and inhibiting the activity of STATs and nuclear hormone receptors. The PIAS -LEF1 interaction was identified through a yeast two-hybrid screen. Overexpression of PIAS resulted in the modification of numerous proteins with SUMO, including LEF1. Mutation of the RING motif of PIAS, a region of functional importance in unbiquitin E3 ligases, decreased PIAS-stimulated sumoylation of cellular proteins. SUMO-modified LEF could still bind to DNA and a transcriptional coactivator, β-catenin, in vitro. Expression of PIAS reduced transcriptional activation of a reporter construct by LEF1 and β-catenin. However, repression of LEF1 by PIAS required the RING domain but not the two consensus sumoylation sites identified in LEF1. PIAS and SUMO expression colocalized in nuclear bodies, and overexpression of PIAS caused relocalization of nuclear LEF1 to these subnuclear regions. The authors suggest that SUMO conjugation of LEF1 may target the transcription factor to nuclear bodies where its activity can be efficiently repressed.

S. Sachdev, L. Bruhn, H. Sieber, A. Pichler, F. Melchior, R. Grosschedl, PIAS, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15, 3088-3103 (2001). [Abstract] [Full Text]