SUMOylation by Pias1 regulates the activity of the Hedgehog dependent Gli transcription factors.
BACKGROUND
Hedgehog (Hh) signaling, a vital signaling pathway for the development and homeostasis of vertebrate tissues, is mediated by members of the Gli family of zinc finger transcription factors. Hh signaling increases the transcriptional activity of Gli proteins, at least in part, by inhibiting their proteolytic processing. Conversely, phosphorylation by cAMP-dependent protein kinase (PKA) inhibits Gli transcriptional activity by promoting their ubiquitination and proteolysis. Whether other post-translational modifications contribute to the regulation of Gli protein activity has been unclear.


RESULTS
Here we provide evidence that all three Gli proteins are targets of small ubiquitin-related modifier (SUMO)-1 conjugation. Expression of SUMO-1 or the SUMO E3 ligase, Pias1, increased Gli transcriptional activity in cultured cells. Moreover, PKA activity reduced Gli protein SUMOylation. Strikingly, in the embryonic neural tube, the forced expression of Pias1 increased Gli activity and induced the ectopic expression of the Gli dependent gene Nkx2.2. Conversely, a point mutant of Pias1, that lacks ligase activity, blocked the endogenous expression of Nkx2.2.


CONCLUSIONS
Together, these findings provide evidence that Pias1-dependent SUMOylation influences Gli protein activity and thereby identifies SUMOylation as a post-translational mechanism that regulates the hedgehog signaling pathway.
Cox
Barny
B
Developmental Neurobiology, Medical Research Council-National Institute for Medical Research, London, United Kingdom.
Briscoe
James
J
Ulloa
Fausto
F
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D054259:Neural Tube / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D014158:Transcription, Genetic; D054875:Ubiquitination
D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; D014157:Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases; D008239:Lysine