Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor

Lasse H. Hansen, Thomas Daugbjerg Madsen, Christoffer K. Goth, Henrik Clausen, Yang Chen, Nina Dzhoyashvili, Seethalakshmi R. Iyer, S Jeson Sangaralingham, John C Jr. Burnett, Jens F. Rehfeld, Sergey Y. Vakhrushev, Katrine T. Schjoldager, Jens P. Goetze

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Atrial natriuretic peptide (ANP) is a peptide hormone that in response to atrial stretch is secreted from atrial myocytes into the circulation, where it stimulates vasodilatation and natriuresis. ANP is an important biomarker of heart failure where low plasma concentrations exclude cardiac dysfunction. ANP is a member of the natriuretic peptide (NP) family, which also includes the B-type natriuretic peptide (BNP) and the C-type natriuretic peptide. The proforms of these hormones undergo processing to mature peptides, and for proBNP, this process has previously been demonstrated to be regulated by O-glycosylation. It has been suggested that proANP also may undergo posttranslational modifications. Here, we conducted a targeted O-glycoproteomics approach to characterize O-glycans on NPs and demonstrate that all NP members can carry O-glycans. We identified four O-glycosites in proANP in the porcine heart, and surprisingly, two of these were located on the mature bioactive ANP itself. We found that one of these glycans is located within a conserved sequence motif of the receptor-binding region, suggesting thatO-glycans may serve a function beyond intracellular processing and maturation. We also identified an O-glycoform of proANP naturally occurring in human circulation. We demonstrated that site-specific O-glycosylation shields bioactive ANP from proteolytic degradation and modifies potency at its cognate receptor in vitro. Furthermore, we showed that ANP O-glycosylation attenuates acute renal and cardiovascular ANP actions in vivo. The discovery of novel glycosylatedANPproteoforms reported here significantly improves our understanding of cardiac endocrinology and provides important insight into the etiology of heart failure.

Original languageEnglish (US)
Pages (from-to)12567-12578
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number34
DOIs
StatePublished - Jan 1 2019

Fingerprint

Atrial Natriuretic Factor
Polysaccharides
Degradation
Glycosylation
Natriuretic Peptides
Endocrinology
Heart Failure
C-Type Natriuretic Peptide
Natriuresis
Peptide Hormones
Conserved Sequence
Brain Natriuretic Peptide
Biomarkers
Post Translational Protein Processing
Processing
Vasodilation
Muscle Cells
Swine
Hormones
Kidney

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor. / Hansen, Lasse H.; Madsen, Thomas Daugbjerg; Goth, Christoffer K.; Clausen, Henrik; Chen, Yang; Dzhoyashvili, Nina; Iyer, Seethalakshmi R.; Sangaralingham, S Jeson; Burnett, John C Jr.; Rehfeld, Jens F.; Vakhrushev, Sergey Y.; Schjoldager, Katrine T.; Goetze, Jens P.

In: Journal of Biological Chemistry, Vol. 294, No. 34, 01.01.2019, p. 12567-12578.

Research output: Contribution to journalReview article

Hansen, LH, Madsen, TD, Goth, CK, Clausen, H, Chen, Y, Dzhoyashvili, N, Iyer, SR, Sangaralingham, SJ, Burnett, JCJ, Rehfeld, JF, Vakhrushev, SY, Schjoldager, KT & Goetze, JP 2019, 'Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor', Journal of Biological Chemistry, vol. 294, no. 34, pp. 12567-12578. https://doi.org/10.1074/jbc.RA119.008102
Hansen, Lasse H. ; Madsen, Thomas Daugbjerg ; Goth, Christoffer K. ; Clausen, Henrik ; Chen, Yang ; Dzhoyashvili, Nina ; Iyer, Seethalakshmi R. ; Sangaralingham, S Jeson ; Burnett, John C Jr. ; Rehfeld, Jens F. ; Vakhrushev, Sergey Y. ; Schjoldager, Katrine T. ; Goetze, Jens P. / Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 34. pp. 12567-12578.
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abstract = "Atrial natriuretic peptide (ANP) is a peptide hormone that in response to atrial stretch is secreted from atrial myocytes into the circulation, where it stimulates vasodilatation and natriuresis. ANP is an important biomarker of heart failure where low plasma concentrations exclude cardiac dysfunction. ANP is a member of the natriuretic peptide (NP) family, which also includes the B-type natriuretic peptide (BNP) and the C-type natriuretic peptide. The proforms of these hormones undergo processing to mature peptides, and for proBNP, this process has previously been demonstrated to be regulated by O-glycosylation. It has been suggested that proANP also may undergo posttranslational modifications. Here, we conducted a targeted O-glycoproteomics approach to characterize O-glycans on NPs and demonstrate that all NP members can carry O-glycans. We identified four O-glycosites in proANP in the porcine heart, and surprisingly, two of these were located on the mature bioactive ANP itself. We found that one of these glycans is located within a conserved sequence motif of the receptor-binding region, suggesting thatO-glycans may serve a function beyond intracellular processing and maturation. We also identified an O-glycoform of proANP naturally occurring in human circulation. We demonstrated that site-specific O-glycosylation shields bioactive ANP from proteolytic degradation and modifies potency at its cognate receptor in vitro. Furthermore, we showed that ANP O-glycosylation attenuates acute renal and cardiovascular ANP actions in vivo. The discovery of novel glycosylatedANPproteoforms reported here significantly improves our understanding of cardiac endocrinology and provides important insight into the etiology of heart failure.",
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AU - Hansen, Lasse H.

AU - Madsen, Thomas Daugbjerg

AU - Goth, Christoffer K.

AU - Clausen, Henrik

AU - Chen, Yang

AU - Dzhoyashvili, Nina

AU - Iyer, Seethalakshmi R.

AU - Sangaralingham, S Jeson

AU - Burnett, John C Jr.

AU - Rehfeld, Jens F.

AU - Vakhrushev, Sergey Y.

AU - Schjoldager, Katrine T.

AU - Goetze, Jens P.

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N2 - Atrial natriuretic peptide (ANP) is a peptide hormone that in response to atrial stretch is secreted from atrial myocytes into the circulation, where it stimulates vasodilatation and natriuresis. ANP is an important biomarker of heart failure where low plasma concentrations exclude cardiac dysfunction. ANP is a member of the natriuretic peptide (NP) family, which also includes the B-type natriuretic peptide (BNP) and the C-type natriuretic peptide. The proforms of these hormones undergo processing to mature peptides, and for proBNP, this process has previously been demonstrated to be regulated by O-glycosylation. It has been suggested that proANP also may undergo posttranslational modifications. Here, we conducted a targeted O-glycoproteomics approach to characterize O-glycans on NPs and demonstrate that all NP members can carry O-glycans. We identified four O-glycosites in proANP in the porcine heart, and surprisingly, two of these were located on the mature bioactive ANP itself. We found that one of these glycans is located within a conserved sequence motif of the receptor-binding region, suggesting thatO-glycans may serve a function beyond intracellular processing and maturation. We also identified an O-glycoform of proANP naturally occurring in human circulation. We demonstrated that site-specific O-glycosylation shields bioactive ANP from proteolytic degradation and modifies potency at its cognate receptor in vitro. Furthermore, we showed that ANP O-glycosylation attenuates acute renal and cardiovascular ANP actions in vivo. The discovery of novel glycosylatedANPproteoforms reported here significantly improves our understanding of cardiac endocrinology and provides important insight into the etiology of heart failure.

AB - Atrial natriuretic peptide (ANP) is a peptide hormone that in response to atrial stretch is secreted from atrial myocytes into the circulation, where it stimulates vasodilatation and natriuresis. ANP is an important biomarker of heart failure where low plasma concentrations exclude cardiac dysfunction. ANP is a member of the natriuretic peptide (NP) family, which also includes the B-type natriuretic peptide (BNP) and the C-type natriuretic peptide. The proforms of these hormones undergo processing to mature peptides, and for proBNP, this process has previously been demonstrated to be regulated by O-glycosylation. It has been suggested that proANP also may undergo posttranslational modifications. Here, we conducted a targeted O-glycoproteomics approach to characterize O-glycans on NPs and demonstrate that all NP members can carry O-glycans. We identified four O-glycosites in proANP in the porcine heart, and surprisingly, two of these were located on the mature bioactive ANP itself. We found that one of these glycans is located within a conserved sequence motif of the receptor-binding region, suggesting thatO-glycans may serve a function beyond intracellular processing and maturation. We also identified an O-glycoform of proANP naturally occurring in human circulation. We demonstrated that site-specific O-glycosylation shields bioactive ANP from proteolytic degradation and modifies potency at its cognate receptor in vitro. Furthermore, we showed that ANP O-glycosylation attenuates acute renal and cardiovascular ANP actions in vivo. The discovery of novel glycosylatedANPproteoforms reported here significantly improves our understanding of cardiac endocrinology and provides important insight into the etiology of heart failure.

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