The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility
Artikel i vetenskaplig tidskrift, 2021

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.

Författare

Charlotte B. Spliid

University of California at San Diego (UCSD)

Köpenhamns universitet

Alejandro Gomez Toledo

University of California at San Diego (UCSD)

Lunds universitet

Patience Sanderson

University of Georgia

Yang Mao

Sun Yat-Sen University

Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research

Francesco Gatto

Chalmers, Biologi och bioteknik, Systembiologi

Tobias Gustavsson

Köpenhamns universitet

Swati Choudhary

Köpenhamns universitet

Ana L. Saldanha

Köpenhamns universitet

Rasmus P. Vogelsang

Sjællands Universitetshospital

Ismail Gögenur

Sjællands Universitetshospital

Thor G. Theander

Köpenhamns universitet

Franklin E. Leach

University of Georgia

I. Jonathan Amster

University of Georgia

Jeffrey D. Esko

University of California at San Diego (UCSD)

Ali Salanti

Köpenhamns universitet

Thomas Mandel Clausen

Köpenhamns universitet

University of California at San Diego (UCSD)

Journal of Biological Chemistry

0021-9258 (ISSN) 1083-351X (eISSN)

Vol. 297 6 101391

Ämneskategorier

Cell- och molekylärbiologi

Immunologi inom det medicinska området

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1016/j.jbc.2021.101391

PubMed

34762909

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Senast uppdaterat

2021-12-20