SUMOylationasamechanismtomodulateCtBPdependentgeneresponses

Covalent attachment of one eukaryotic protein to another is a prominent posttranslational modification and Ubiquitin is the most familiar of the protein modifiers. Recently a new group of ubiquitin-like (Ubl) proteins have come to light. One of the most intriguing of them is SUMO (small ubiquitin-like modifier, ~12kDa) also known as Sentrin. SUMO family has been described in vertebrates: SUMO-1 and the closest homologs SUMO-2 and SUMO-3. SUMO have been shown to bind and regulate mammalian SP-RINGs (such as Mdm2, PIAS and PML), RanGAP1, RanBP2, p53, p73, HIPK2, TEL, c-Jun, CtBP, Fas, Daxx, TNFRI, Topo-I, Topo-II, WRN, Sp100, IkB-alpha, Androgen receptor (AR), GLUT1/4, Drosophila Ttk69, Dorsal, CaMK, yeast Septins, and viral CMV-IE1/2, EBV-BZLF1, HPV/BPV-E1. In the case of the transcription co-repressor CtBP, which can be recruited to the target promoter via interaction with a conserved PxDLS motif in the interacting repressor, CtBP SUMOylation profoundly affected its subcellular localization. SUMOylation occurred at a single Lys residue, Lys428, of CtBP1. Mutating Lys428 into Arg (K428R) shifted CtBP1 from the nucleus to the cytoplasm, while it had little effect on its interaction with the PxDLS motif. The K428R mutation also abolished the ability of CtBP1 to repress the E-cadherin promoter activity. Consistent with the known inhibitory effect of nNOS on the nuclear accumulation of CtBP1, PDZ domain of nNOS inhibits the SUMOylation of CtBP1. The current data indicates that SUMOylation can regulate CtBP1-dependent transcriptional repression.

Contributor: Kosi Gramatikoff, PhD

REFERENCES: Bayer P et al. Structure determination of the small ubiquitin-related modifier SUMO-1.1998. J. Mol. Biol. 280(2): 275-86. Lin, X et al., Short Article Opposed Regulation of Corepressor CtBP by SUMOylation and PDZ Binding Molecular Cell, Vol. 11, 1389–1396, May, 2003 Muller, S. et al. SUMO, ubiquitin's mysterious cousin. 2001. Nat. Rev. Mol. Cell Biol. 2:202-210.