Régulation de l'expression du gène de l'argininosuccinate synthétase par la glutamine et l'interleukine-1beta dans la lignée entérocytaire Caco-2

Argininosuccinate synthetase (ASS), the limiting enzyme of arginine synthesis can be stimulated by glutamine and proinflammatory factors but their molecular mechanism of action on the expression of this gene was unknown. In the present study, using Caco-2 cells, a human intestinal cell line, it is demonstrated that the metabolism of glutamine through the hexosamine pathway leads to the cytosolic O-glycosylation of the transcription factor Sp1, witch in turn, can translocate into nucleus and bind to DNA to stimulates the ASS gene transcription. Moreover, we demonstrate that IL-1b rapidly induces the expression of the ASS gene at a transcriptional level through NF-kB activation and this factor may interact with the ASS gene promoter. Thereafter, the IL-1b-induced production of nitric oxide inhibits the activity of ASS by a post translational mechanism. Finally, when glutamine was added together with IL-1b, the stimulating effects of both inducers appeared mutually inhibited. Concerning the molecular mechanism involved, using glucosamine, we show that Sp1 might be a key of this interaction. We suggest that IL-1b increased the serine phosphorylation of Sp1 protein and this event might block its activation by O-glycosylation.