SUMOylation of the lens epithelium-derived growth factor/p75 attenuates its transcriptional activity on the heat shock protein 27 promoter.
Lens epithelium-derived growth factor (LEDGF) proteins p75 and p52 are transcriptional coactivators that connect sequence-specific activators to the basal transcription machinery. We have found that these proteins are posttranslationally modified by SUMO (small ubiquitin-like modifier)-1 and SUMO-3. Three SUMOylation sites, K75, K250, and K254, were mapped on the shared N-terminal region of these molecules, while a fourth site, K364, was identified in the C-terminal part exclusive of LEDGF/p75. The N-terminal SUMO targets are located in evolutionarily conserved charge-rich regions that lack resemblance to the described consensus SUMOylation motif, whereas the C-terminal SUMO target is solvent exposed and situated in a typical consensus motif. SUMOylation did not affect the cellular localization of LEDGF proteins and was not necessary for their chromatin-binding ability, nor did it affect this activity. However, lysine to arginine mutations of the identified SUMO acceptor sites drastically inhibited LEDGF SUMOylation, extended the half-life of LEDGF/p75, and significantly increased its transcriptional activity on the heat shock protein 27 promoter, indicating a negative effect of SUMOylation on the transcriptional activity of LEDGF/p75. Considering that SUMOylation is known to negatively affect the transcriptional activity of all transcription factors known to transactivate heat shock protein 27 expression, these findings support the paradigm establishing SUMOylation as a global neutralizer of cellular processes upregulated upon cellular stress.
Bueno
Murilo T D
MT
Department of Biological Sciences, University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968, USA.
Garcia-Rivera
Jose A
JA
Kugelman
Jeffrey R
JR
Morales
Elisa
E
Rosas-Acosta
Germán
G
Llano
Manuel
M
D019943:Amino Acid Substitution; D002460:Cell Line; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis*; D006207:Half-Life; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014452:Ubiquitins / Q000378:metabolism*
D055551:HSP27 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D025842:SUMO-1 Protein; C492189:SUMO3 protein, human; D014157:Transcription Factors; D014452:Ubiquitins; C119380:lens epithelium-derived growth factor
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