Structural organization of erythrocyte membrane microdomains and their relation with malaria susceptibility

Anna Olivieri,Stefania Bertoncini,Valentina Tirelli,Rebecca S Lee ,Manoj T Duraisingh,Estela Shabani,Federica Fratini,Cecilia Birago,Stefania Mochi,Elisabetta Pizzi,Valentina Mangano ,Felicia Grasso,Cyrianne Keutcha,Mudit Chaand,Mario Falchi,David Modiano,Bienvenu Sodiomon Sirima ,Silvio Paone,Francesco Celani ,Marta Ponzi

doi:10.1038/s42003-021-02900-w

Abstract

Cholesterol-rich microdomains are membrane compartments characterized by specific lipid and protein composition. These dynamic assemblies are involved in several biological processes, including infection by intracellular pathogens. This work provides a comprehensive analysis of the composition of human erythrocyte membrane microdomains. Based on their floating properties, we also categorized the microdomain-associated proteins into clusters. Interestingly, erythrocyte microdomains include the vast majority of the proteins known to be involved in invasion by the malaria parasite Plasmodium falciparum. We show here that the Ecto-ADP-ribosyltransferase 4 (ART4) and Aquaporin 1 (AQP1), found within one specific cluster, containing the essential host determinant CD55, are recruited to the site of parasite entry and then internalized to the newly formed parasitophorous vacuole membrane. By generating null erythroid cell lines, we showed that one of these proteins, ART4, plays a role in P. falciparum invasion. We also found that genetic variants in both ART4 and AQP1 are associated with susceptibility to the disease in a malaria-endemic population.

Highlights

Cholesterol-rich microdomains are membrane compartments characterized by specific lipid and protein composition
We focused in particular on cluster 3, containing the blood group CD55 and two proteins previously described as highranking candidates for being involved in invasion, Ecto-ADPribosyltransferase 4 (ART4) and Aquaporin 1 (AQP1)[8]
Biochemical characterization of cholesterol-rich membrane microdomains relies on their resistance to solubilization by certain non-ionic detergents at low temperature, which allows to isolate them as detergent-resistant membranes (DRMs) by sucrose gradient centrifugation

Summary

Introduction

Cholesterol-rich microdomains are membrane compartments characterized by specific lipid and protein composition These dynamic assemblies are involved in several biological processes, including infection by intracellular pathogens. Erythrocyte microdomains include the vast majority of the proteins known to be involved in invasion by the malaria parasite Plasmodium falciparum. The vast majority of the lethal events due to malaria are caused by the parasite Plasmodium falciparum This pathogen develops and replicates inside hepatocytes during the silent phase of infection and inside erythrocytes during the clinical phase. An essential role of erythrocyte membrane microdomains in susceptibility to invasion by the malaria parasite P. falciparum was suggested by the reports that modification[5] or disruption[3] of these subcellular compartments prevent invasion by merozoites. Despite the proved role of host cholesterol-rich microdomains in malaria pathogenesis, only a few proteins associated with these membrane compartments have been characterized so far[6]

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