Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

Rivas, Matilde de las; Daniel, Earnest James Paul; Narimatsu, Yoshiki; Compañón, Ismael; Kato, Kentaro; Hermosilla, Pablo; Thureau, Aurélien; Ceballos-Laita, Laura; Coelho, Helena; Bernadó, Pau; Marcelo, Filipa; Hansen, Lars; Maeda, Ryota; Lostao, Anabel; Corzana, Francisco; Clausen, Henrik; Gerken, Thomas A.; Hurtado‐Guerrero, R.

doi:10.1038/s41589-019-0444-x

Cited by 59 publications

(55 citation statements)

References 60 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the four newly discovered O-glycosylation sites, two reside in the furin cleavage site between S1/S2 (Thr678 and Ser686) which are unique to SARS-CoV-2. Although there has not yet been evidence that O-glycosylation plays a role in protease cleavage of S 1 , 29 , further investigation is warranted as O-glycosylation does affect protease susceptibility in other systems, as well as antibody recognition 30 , 31 .…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

Gao

Zeng

Jia

et al. 2020

Preprint

111

149

View full text Add to dashboard Cite

The spike (S) glycoprotein in the envelope of SARS-CoV-2 is densely glycosylated but the functions of its glycosylation are unknown. Here we demonstrate that S is recognized in a glycan-dependent manner by multiple innate immune receptors including the mannose receptor MR/CD206, DC-SIGN/CD209, L-SIGN/CD209L, and MGL/CLEC10A/CD301. Single-cell RNA sequencing analyses indicate that such receptors are highly expressed in innate immune cells in tissues susceptible to SARS-CoV-2 infection. Binding of the above receptors to S is characterized by affinities in the picomolar range and consistent with S glycosylation analysis demonstrating a variety of N- and O-glycans as receptor ligands. These results indicate multiple routes for SARS-CoV-2 to interact with human cells and suggest alternative strategies for therapeutic intervention.

show abstract

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

Gao

Zeng

Jia

et al. 2020

Preprint

111

149

View full text Add to dashboard Cite

show abstract

“…2005; de las Rivas et al . 2020), and of Phex , an endopeptidase that indirectly downregulates FGF23 protein abundance (Liu et al . 2003), were not modified.…”

Section: Discussionmentioning

confidence: 99%

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

Hernando

Pastor-Arroyo

Marks

et al. 2020

The Journal of Physiology

View full text Add to dashboard Cite

Key points Intestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi‐IIb/Slc34a2 and a poorly characterized passive/paracellular pathway. Intestinal phosphate absorption and expression of NaPi‐IIb are stimulated by 1,25(OH)2 vitamin D3 but whether NaPi‐IIb is the only target under hormonal control remains unknown. We report that administration of 1,25(OH)2 vitamin D3 to wild‐type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes. Instead, the same treatment failed to alter phosphate transport in intestinal‐depleted Slc34a2‐deficient mice. In both genotypes, 1,25(OH)2 vitamin D3 induced similar hyperphosphaturic responses and changes in the plasma levels of FGF23 and PTH. While urinary phosphate loss induced by administration of 1,25(OH)2 vitamin D3 did not alter plasma phosphate, further studies should investigate whether chronic administration would lead to phosphate imbalance in mice with reduced active intestinal absorption. Abstract Intestinal absorption of phosphate is stimulated by 1,25(OH)2 vitamin D3. At least two distinct mechanisms underlie phosphate absorption in the gut, an active transcellular transport requiring the Na+/phosphate cotransporter NaPi‐IIb/Slc34a2, and a poorly characterized paracellular passive pathway. 1,25(OH)2 vitamin D3 stimulates NaPi‐IIb expression and function, and loss of NaPi‐IIb reduces intestinal phosphate absorption. However, it is remains unknown whether NaPi‐IIb is the only target for hormonal regulation by 1,25(OH)2 vitamin D3. Here we compared the effects of intraperitoneal administration of 1,25(OH)2 vitamin D3 (2 days, once per day) in wild‐type and intestinal‐specific Slc34a2‐deficient mice, and analysed trans‐ vs. paracellular routes of phosphate absorption. We found that treatment stimulated active transport of phosphate only in jejunum of wild‐type mice, though NaPi‐IIb protein expression was upregulated in jejunum and ileum. In contrast, 1,25(OH)2 vitamin D3 administration had no effect in Slc34a2‐deficient mice, suggesting that the hormone specifically regulates NaPi‐IIb expression. In both groups, 1,25(OH)2 vitamin D3 elicited the expected increase of plasma fibroblast growth factor 23 (FGF23) and reduction of parathyroid hormone (PTH). Treatment resulted in hyperphosphaturia (and hypercalciuria) in both genotypes, though mice remained normophosphataemic. While increased intestinal absorption and higher FGF23 can trigger the hyperphosphaturic response in wild types, only higher FGF23 can explain the renal response in Slc34a2‐deficient mice. Thus, 1,25(OH)2 vitamin D3 stimulates intestinal phosphate absorption by acting on the active transcellular pathway mostly mediated by NaPi‐IIb while the paracellular pathway appears not to be affected.

show abstract

“…In a recent study, Thr 178 was identified as a poor substrate site with limited glycosylation acceptance, likely a protective mechanism to prevent cellular resistances to FGF23 cleavage. Interestingly, Thr 178 glycosylation was shown to require a previous glycosylation at Thr 171 before generating a furin-resistant and secreted stable iFGF23 ( 99 ) ( Figure 2 ). These new discoveries suggest that GALNT3 specificity for FGF23 and its ability to control circulating levels of bioactive FGF23 is a control point achieved by FGF23 being a rather poor substrate for this enzyme ( 99 ).…”

Section: Fgf23 Cleavage: a Physiological And Endogenous Mechanism To mentioning

confidence: 99%

“…Interestingly, Thr 178 glycosylation was shown to require a previous glycosylation at Thr 171 before generating a furin-resistant and secreted stable iFGF23 ( 99 ) ( Figure 2 ). These new discoveries suggest that GALNT3 specificity for FGF23 and its ability to control circulating levels of bioactive FGF23 is a control point achieved by FGF23 being a rather poor substrate for this enzyme ( 99 ). In contrast to the O -glycosylation induced by GALNT3 which stabilizes FGF23, the phosphorylation at position S 180 by the kinase FAM20C inhibited O -glycosylation of FGF23, thus promoting FGF23 cleavage ( 98 ) ( Figure 2 ).…”

Section: Fgf23 Cleavage: a Physiological And Endogenous Mechanism To mentioning

confidence: 99%

Osteocytic FGF23 and Its Kidney Function

Agoro

Noonan

et al. 2020

Front. Endocrinol.

View full text Add to dashboard Cite

Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH) 2 vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia via a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.

show abstract

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

Cited by 59 publications

References 60 publications

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

Osteocytic FGF23 and Its Kidney Function

Contact Info

Product

Resources

About

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3

Cited by 59 publications

References 60 publications

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

Osteocytic FGF23 and Its Kidney Function

Contact Info

Product

Resources

About

1,25(OH)₂ vitamin D₃ stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine