Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

DOI

  1. Using Self-Rated Examinations to Ensure Competence in Laparoscopy

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  2. Deep Learning identifies inflamed fat as a risk factor for lymph node metastasis in early colorectal cancer

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  3. Physical activity after colorectal cancer surgery-a cross sectional study of patients with a long-term stoma

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

Vis graf over relationer

Placental malaria infection is mediated by the binding of the malarial VAR2CSA protein to the placental glycosaminoglycan, chondroitin sulfate. Recombinant subfragments of VAR2CSA (rVAR2) have also been shown to bind specifically and with high affinity to cancer cells and tissues, suggesting the presence of a shared type of oncofetal chondroitin sulfate (ofCS) in the placenta and in tumors. However, the exact structure of ofCS and what determines the selective tropism of VAR2CSA remains poorly understood. In this study, ofCS was purified by affinity chromatography using rVAR2 and subjected to detailed structural analysis. We found high levels of N-acetylgalactosamine 4-O-sulfation (∼80-85%) in placenta- and tumor-derived ofCS. This level of 4-O-sulfation was also found in other tissues that do not support parasite sequestration, suggesting that VAR2CSA tropism is not exclusively determined by placenta- and tumor-specific sulfation. Here, we show that both placenta and tumors contain significantly more chondroitin sulfate moieties of higher molecular weight than other tissues. In line with this, CHPF and CHPF2, which encode proteins required for chondroitin polymerization, are significantly upregulated in most cancer types. CRISPR/Cas9 targeting of CHPF and CHPF2 in tumor cells reduced the average molecular weight of cell-surface chondroitin sulfate and resulted in a marked reduction of rVAR2 binding. Finally, utilizing a cell-based glycocalyx model, we showed that rVAR2 binding correlates with the length of the chondroitin sulfate chains in the cellular glycocalyx. These data demonstrate that the total amount and cellular accessibility of chondroitin sulfate chains impact rVAR2 binding and thus malaria infection.

OriginalsprogEngelsk
Artikelnummer101391
TidsskriftJournal of Biological Chemistry
Vol/bind297
Udgave nummer6
Sider (fra-til)101391
ISSN0021-9258
DOI
StatusUdgivet - dec. 2021

Bibliografisk note

Published by Elsevier Inc.

ID: 75139183