Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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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.; Rehfeld, Jens F.; Vakhrushev, Sergey Y.; Schjoldager, Katrine T.; Goetze, Jens P.
I: Journal of Biological Chemistry, Bind 294, Nr. 34, 2019, s. 12567-12578.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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T1 - Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor
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.
AU - Rehfeld, Jens F.
AU - Vakhrushev, Sergey Y.
AU - Schjoldager, Katrine T.
AU - Goetze, Jens P.
PY - 2019
Y1 - 2019
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.
U2 - 10.1074/jbc.RA119.008102
DO - 10.1074/jbc.RA119.008102
M3 - Review
C2 - 31186350
AN - SCOPUS:85071484729
VL - 294
SP - 12567
EP - 12578
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 34
ER -
ID: 227470162