A Golgi-associated redox switch regulates catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I
Identifieur interne : 000064 ( France/Analysis ); précédent : 000063; suivant : 000065A Golgi-associated redox switch regulates catalytic activation and cooperative functioning of ST6Gal-I with B4GalT-I
Auteurs : Antti Hassinen [Finlande] ; Fawzi Khoder-Agha [Finlande] ; Elham Khosrowabadi [Finlande] ; Daniela Mennerich [Finlande] ; Deborah Harrus [Finlande] ; Maxence Noel [France] ; Elitsa Y. Dimova [Finlande] ; Tuomo Glumoff [Finlande] ; Anne Harduin-Lepers [France] ; Thomas Kietzmann [Finlande] ; Sakari Kellokumpu [Finlande]Source :
- Redox Biology [ 2213-2317 ] ; 2019.
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.
Url:
DOI: 10.1016/j.redox.2019.101182
PubMed: 30959459
PubMed Central: 6454061
Affiliations:
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last="Hassinen">Antti Hassinen</name><affiliation wicri:level="1"><nlm:aff id="aff1">University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Khoder Agha, Fawzi" sort="Khoder Agha, Fawzi" uniqKey="Khoder Agha F" first="Fawzi" last="Khoder-Agha">Fawzi Khoder-Agha</name><affiliation wicri:level="1"><nlm:aff id="aff1">University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Khosrowabadi, Elham" sort="Khosrowabadi, Elham" uniqKey="Khosrowabadi E" first="Elham" last="Khosrowabadi">Elham Khosrowabadi</name><affiliation wicri:level="1"><nlm:aff id="aff1">University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Mennerich, Daniela" sort="Mennerich, Daniela" uniqKey="Mennerich D" first="Daniela" last="Mennerich">Daniela Mennerich</name><affiliation wicri:level="1"><nlm:aff id="aff1">University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Harrus, Deborah" sort="Harrus, Deborah" uniqKey="Harrus D" first="Deborah" last="Harrus">Deborah Harrus</name><affiliation wicri:level="1"><nlm:aff id="aff1">University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>University of Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu</wicri:regionArea><wicri:noRegion>Oulu</wicri:noRegion></affiliation></author><author><name sortKey="Noel, Maxence" sort="Noel, Maxence" uniqKey="Noel M" first="Maxence" last="Noel">Maxence Noel</name><affiliation wicri:level="3"><nlm:aff id="aff2">Université de Lille, CNRS, UMR 8576, UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université de Lille, CNRS, UMR 8576, UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille</wicri:regionArea><placeName><region type="region" nuts="2">Hauts-de-France</region><region type="old region" nuts="2">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Dimova, Elitsa Y" sort="Dimova, Elitsa Y" uniqKey="Dimova E" first="Elitsa Y." last="Dimova">Elitsa Y. 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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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Varki, A" uniqKey="Varki A">A. Varki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hakomori, S" uniqKey="Hakomori S">S. Hakomori</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fuster, M M" uniqKey="Fuster M">M.M. Fuster</name></author><author><name sortKey="Esko, J D" uniqKey="Esko J">J.D. 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Yodoi</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Finlande</li><li>France</li></country><region><li>Hauts-de-France</li><li>Nord-Pas-de-Calais</li></region><settlement><li>Lille</li></settlement></list><tree><country name="Finlande"><noRegion><name sortKey="Hassinen, Antti" sort="Hassinen, Antti" uniqKey="Hassinen A" first="Antti" last="Hassinen">Antti Hassinen</name></noRegion><name sortKey="Dimova, Elitsa Y" sort="Dimova, Elitsa Y" uniqKey="Dimova E" first="Elitsa Y." last="Dimova">Elitsa Y. Dimova</name><name sortKey="Glumoff, Tuomo" sort="Glumoff, Tuomo" uniqKey="Glumoff T" first="Tuomo" last="Glumoff">Tuomo Glumoff</name><name sortKey="Harrus, Deborah" sort="Harrus, Deborah" uniqKey="Harrus D" first="Deborah" last="Harrus">Deborah Harrus</name><name sortKey="Kellokumpu, Sakari" sort="Kellokumpu, Sakari" uniqKey="Kellokumpu S" first="Sakari" last="Kellokumpu">Sakari Kellokumpu</name><name sortKey="Khoder Agha, Fawzi" sort="Khoder Agha, Fawzi" uniqKey="Khoder Agha F" first="Fawzi" last="Khoder-Agha">Fawzi Khoder-Agha</name><name sortKey="Khosrowabadi, Elham" sort="Khosrowabadi, Elham" uniqKey="Khosrowabadi E" first="Elham" last="Khosrowabadi">Elham Khosrowabadi</name><name sortKey="Kietzmann, Thomas" sort="Kietzmann, Thomas" uniqKey="Kietzmann T" first="Thomas" last="Kietzmann">Thomas Kietzmann</name><name sortKey="Mennerich, Daniela" sort="Mennerich, Daniela" uniqKey="Mennerich D" first="Daniela" last="Mennerich">Daniela Mennerich</name></country><country name="France"><region name="Hauts-de-France"><name sortKey="Noel, Maxence" sort="Noel, Maxence" uniqKey="Noel M" first="Maxence" last="Noel">Maxence Noel</name></region><name sortKey="Harduin Lepers, Anne" sort="Harduin Lepers, Anne" uniqKey="Harduin Lepers A" first="Anne" last="Harduin-Lepers">Anne Harduin-Lepers</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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