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Redox Biol. 2019 Jun;24:101182. doi: 10.1016/j.redox.2019.101182. Epub 2019 Apr 4.

A Golgi-associated redox switch regulates catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I.

Author information

1
University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland.
2
Université de Lille, CNRS, UMR 8576, UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France.
3
University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland. Electronic address: sakari.kellokumpu@oulu.fi.

Abstract

Glycosylation, a common modification of cellular proteins and lipids, is often altered in diseases and pathophysiological states such as hypoxia, yet the underlying molecular causes remain poorly understood. By utilizing lectin microarray glycan profiling, Golgi pH and redox screens, we show here that hypoxia inhibits terminal sialylation of N- and O-linked glycans in a HIF- independent manner by lowering Golgi oxidative potential. This redox state change was accompanied by loss of two surface-exposed disulfide bonds in the catalytic domain of the α-2,6-sialyltransferase (ST6Gal-I) and its ability to functionally interact with B4GalT-I, an enzyme adding the preceding galactose to complex N-glycans. Mutagenesis of selected cysteine residues in ST6Gal-I mimicked these effects, and also rendered the enzyme inactive. Cells expressing the inactive mutant, but not those expressing the wild type ST6Gal-I, were able to proliferate and migrate normally, supporting the view that inactivation of the ST6Gal-I help cells to adapt to hypoxic environment. Structure comparisons revealed similar disulfide bonds also in ST3Gal-I, suggesting that this O-glycan and glycolipid modifying sialyltransferase is also sensitive to hypoxia and thereby contribute to attenuated sialylation of O-linked glycans in hypoxic cells. Collectively, these findings unveil a previously unknown redox switch in the Golgi apparatus that is responsible for the catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I.

KEYWORDS:

Glycosylation; Golgi homeostasis; Hypoxia; Redox state; Sialyltransferase

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