Podoplanin requires sialylated O-glycans for stable expression on lymphatic endothelial cells and for interaction with platelets

Yanfang Pan, Tadayuki Yago, Jianxin Fu, Brett Herzog, J. Michael McDaniel, Padmaja Mehta-D'Souza, Xiaofeng Cai, Changgeng Ruan, Rodger P. McEver, Christopher West, Kesheng Dai, Hong Chen, Lijun Xia

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

O-glycosylation of podoplanin (PDPN) on lymphatic endothelial cells is critical for the separation of blood and lymphatic systems by interacting with platelet C-type lectin-like receptor 2 during development. However, how O-glycosylation controls endothelial PDPN function and expression remains unclear. In this study, we report that core 1 O-glycan-deficient or desialylated PDPN was highly susceptible to proteolytic degradation by various proteases, including metalloproteinases (MMP)-2/9. We found that the lymph contained activated MMP-2/9 and incubation of the lymph reduced surface levels of PDPN on core 1 O-glycan-deficient endothelial cells, but not on wild-type ECs. The lymph from mice with sepsis induced by cecal ligation and puncture, which contained bacteriaderived sialidase, reduced PDPN levels on wild-type ECs. The MMP inhibitor, GM6001, rescued these reductions. Additionally, GM6001 treatment rescued the reduction of PDPN level on lymphatic endothelial cells in mice lacking endothelial core 1 O-glycan or cecal ligation and puncture-treated mice. Furthermore, core 1 O-glycan-deficient or desialylated PDPN impaired platelet interaction under physiological flow. These data indicate that sialylated O-glycans of PDPN are essential for platelet adhesion and prevent PDPN from proteolytic degradation primarily mediated by MMPs in the lymph.

Original languageEnglish
Pages (from-to)3656-3665
Number of pages10
JournalBlood
Volume124
Issue number24
DOIs
StatePublished - Dec 4 2014

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