Abstract
The intracellular regulation of HA synthesis throughout O‐GlcNacylation is investigated. It was reported that the HA precursor UDP‐N‐acetylglucosamine (UDP‐GlcNac) and UDP glucuronic acid availability modulates of HA synthesis. In this study, we tested the role of O‐GlcNacylation, a type of cytoplasmic protein O‐glycosylation to ser/thr residues and its influence on hyaluronan synthase activity. We found that the inhibition of OGlcNacylation strongly reduced HA production whereas treatments that induced protein O‐GlcNacylation increased HA secretion. Gene expression studies revealed that HAS2 mRNA (i.e., the main HA synthesizing enzyme located in the plasma membrane) was the most sensible to O‐GlcNacylation and accumulated after its induction. We found evidences that the transcription regulator YY1 activates HAS2 expression after O‐GlcNacylation. At protein level, experiments with wheat germ agglutinin and recombinant 6myc‐HAS2 revealed that this enzyme was actually O‐GlcNacylated. Further, HAS2 O‐GlcNacylation increased HAS activity in purified microsomes leading to HA accumulation. Interestingly, the O‐GlcNacylation was able to delay the protein removal from cell membrane increasing the enzyme turn‐over, another way to induce increase of HA. This work was supported by FAR and Onlus Varesotto‐ITALY.
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