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

• Published in: Communications biology 2021-12, Vol.4 (1), p.1375-1375, Article 1375
• Main Authors: Olivieri, Anna, Lee, Rebecca S., Fratini, Federica, Keutcha, Cyrianne, Chaand, Mudit, Mangano, Valentina, Celani, Francesco, Mochi, Stefania, Birago, Cecilia, Paone, Silvio, Grasso, Felicia, Tirelli, Valentina, Falchi, Mario, Shabani, Estela, Bertoncini, Stefania, Sirima, Bienvenu Sodiomon, Pizzi, Elisabetta, Modiano, David, Duraisingh, Manoj T., Ponzi, Marta
• Format: Article
• Language: English
• Subjects: 101/58; 14/19; 14/34; 14/63; 38/1; 38/39; 45/23; 45/41; 631/326/417/2546; 692/699/255/1629; 82/29; 96/31; Aquaporin 1; Biology; Biomedical and Life Sciences; Cell lines; Cholesterol; Erythrocyte Membrane - chemistry; Erythrocyte Membrane - parasitology; Erythrocytes; Erythrocytes - chemistry; Erythrocytes - parasitology; Genetic diversity; Humans; Life Sciences; Malaria; Malaria - parasitology; Malaria, Falciparum - parasitology; Membrane Microdomains - chemistry; Parasitophorous vacuole; Plasmodium falciparum; Plasmodium falciparum - physiology; Protein composition; Proteins; Proteomics
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02900-w

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. Olivieri et al. exploit floating properties of microdomain-associated proteins to investigate host proteins important for Plasmodium falciparum erythrocyte invasion. Using proteomic and bioinformatic approaches, they analyze clusters of protein abundance profiles from detergent resistant membranes (DRMs) of erythrocytes and identify a host protein, ART4, important for P. falciparum invasion into RBCs.