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Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

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  • Christoffer K Goth
  • Hanna E Tuhkanen
  • Hamayun Khan
  • Jarkko J Lackman
  • Shengjun Wang
  • Yoshiki Narimatsu
  • Lasse H Hansen
  • Christopher M Overall
  • Henrik Clausen
  • Katrine T Schjoldager
  • Ulla E Petäjä-Repo
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The β1-adrenergic receptor (β1AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for β-adrenergic antagonists, such as β-blockers, relatively little is yet known about its regulation. We have shown previously that β1AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation and, moreover, that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates β1AR at five residues in the extracellular N terminus, including the Ser-49 residue at the location of the common S49G single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T-edited cell line model systems, and a GalNAc-T2 knock-out rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of β1AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis lead to attenuated receptor signaling, because the maximal response elicited by the βAR agonist isoproterenol and its potency in a cAMP accumulation assay were decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of β1AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases.

Original languageEnglish
JournalThe journal of biological chemistry
Issue number11
Pages (from-to)4714-4726
Number of pages13
Publication statusPublished - 17 Mar 2017

    Research areas

  • Amino Acid Sequence, Animals, Gene Knockout Techniques, Glycosylation, HEK293 Cells, Hep G2 Cells, Humans, N-Acetylgalactosaminyltransferases, Polymorphism, Single Nucleotide, Protein Isoforms, Proteolysis, Rats, Receptors, Adrenergic, beta-1, Journal Article

ID: 52054077