Autophagy regulates hyaluronan synthase 2 levels in vascular endothelial cells

Chen, C. G.; Gubbiotti, M. A.; Han, X.; Yu, Y.; Linhardt, R. J.; Iozzo, R. V.

doi:10.1101/413948

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bioRxiv · 10.1101/413948

Autophagy regulates hyaluronan synthase 2 levels in vascular endothelial cells

Chen, C. G.·Gubbiotti, M. A.·Han, X.·Yu, Y.·Linhardt, R. J.·Iozzo, R. V.

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Abstract

Hyaluronan is emerging as a key player regulating wound repair, inflammation, and angiogenesis. Of the three hyaluronan synthases (HAS1-3), HAS2 is the main driver of tumorigenicity by enhancing hyaluronan deposition. We discovered that HAS2 was degraded in vascular endothelial cells via autophagy, a catabolic process evoked by endorepellin and endostatin, two angiostatic and pro-autophagic effectors, and by Torin 1, a specific mTOR inhibitor. Protracted autophagy increased co-localization of HAS2 with three core components of the autophagosome, LC3, p62, and ATG9A, and binding of HAS2 to ATG9A. Importantly, autophagic induction led to an exclusive and marked suppression of secreted hyaluronan with no significant effects on either heparan or chondroitin sulfate levels. Thus, we have unveiled autophagy as a key catabolic mechanism regulating the production of hyaluronan in endothelial cells. Moreover, our study provides a biological link between autophagy and angiogenesis that could lead to potential targets for tumor neovascularization.\n\nSummaryHyaluronan is pro-angiogenic and pro-tumorigenic. We report a novel mechanism through which three autophagic inducers[-]endorepellin, endostatin, and Torin 1[-]regulate the levels of hyaluronan synthase-2. Protracted autophagy results in suppression of extracellular hyaluronan, thereby implicating autophagy in the regulation hyaluronan production.

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Chen, C. G., Gubbiotti, M. A., Han, X., Yu, Y., Linhardt, R. J., Iozzo, R. V.. 2018-09-10. Autophagy regulates hyaluronan synthase 2 levels in vascular endothelial cells. https://doi.org/10.1101/413948

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