Identification of DPY19L3 as the C-mannosyltransferase of R-spondin1 in human cells

Molecular Biology of the Cell
Yuki NiwaSiro Simizu

Abstract

R-spondin1 (Rspo1) is a secreted protein that enhances Wnt signaling, which has crucial functions in embryonic development and several cancers. C-mannosylation is a rare type of glycosylation and might regulate secretion, protein-protein interactions, and enzymatic activity. Although human Rspo1 contains 2 predicted C-mannosylation sites, C-mannosylation of Rspo1 has not been reported, nor have its functional effects on this protein. In this study, we demonstrate by mass spectrometry that Rspo1 is C-mannosylated at W(153) and W(156). Using Lec15.2 cells, which lack dolichol-phosphate-mannose synthesis activity, and mutant Rspo1-expressing cells that replace W(153) and W(156) by alanine residues, we observed that C-mannosylation of Rspo1 is required for its secretion. Further, the enhancement of canonical Wnt signaling by Rspo1 is regulated by C-mannosylation. Recently DPY19 was reported to be a C-mannosyltransferase in Caenorhabditis elegans, but no C-mannosyltransferases have been identified in any other organism. In gain- and loss-of-function experiments, human DPY19L3 selectively modified Rspo1 at W(156) but not W(153) based on mass spectrometry. Moreover, knockdown of DPY19L3 inhibited the secretion of Rspo1. In conclusion,...Continue Reading

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Citations

Sep 27, 2016·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Ryan P BergerStephen Dalton
Feb 7, 2018·The FEBS Journal·Yuki NiwaSiro Simizu
Feb 19, 2019·Parasitology·Giulia BandiniFrançoise H Routier
Dec 22, 2019·The Journal of Biological Chemistry·Andreia Albuquerque-WendtFrançoise H Routier
Dec 31, 2019·Oncology Letters·Naoyuki IwahashiYoshito Ihara
Aug 18, 2020·Glycoconjugate Journal·Shiho MinakataYoshito Ihara
Feb 17, 2017·Proceedings of the National Academy of Sciences of the United States of America·Aleksandra ShcherbakovaHans Bakker
Dec 24, 2019·ELife·Aleksandra ShcherbakovaHans Bakker
Jan 8, 2021·Biochimica Et Biophysica Acta. General Subjects·Satoshi YoshimotoSiro Simizu
Feb 6, 2021·Nature Chemical Biology·Alan JohnEthan D Goddard-Borger
May 18, 2020·Biochimica Et Biophysica Acta. General Subjects·Yoko InaiYoshito Ihara
Mar 5, 2018·Biochemical and Biophysical Research Communications·Kei OtaniSiro Simizu
May 12, 2021·Molecular & Cellular Proteomics : MCP·Karsten CirksenaFalk F R Buettner

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Methods Mentioned

BETA
fluorescence microscopy
PCR
transfection

Software Mentioned

ImageJ
Rspos
TOPFlash
MASCOT

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