Phosphorylation of the VAR2CSA extracellular region is associated with enhanced adhesive properties to the placental receptor CSA
Dominique Dorin-Semblat
(1, 2)
,
Marilou Tétard
(1, 2)
,
Aurélie Claës
(3)
,
Jean-Philippe Semblat
(1, 2)
,
Sébastien Dechavanne
(1, 2)
,
Zaineb Fourati
(1, 2)
,
Romain Hamelin
(4)
,
Florence Armand
(4)
,
Graziella Matesic
(1, 2)
,
Sofia Nunes-Silva
(1, 2)
,
Anand Srivastava
(1, 2)
,
Stéphane Gangnard
(1, 2)
,
Jose-Juan Lopez-Rubio
(5)
,
Marc Moniatte
(4)
,
Christian Doerig
(6)
,
Artur Scherf
(3)
,
Benoît Gamain
(1, 2)
1
BIGR (UMR_S_1134 / U1134) -
Biologie Intégrée du Globule Rouge
2 INTS - Institut National de la Transfusion Sanguine [Paris]
3 Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions
4 Proteomics Core Facility [Lausanne, Suisse]
5 MIVEGEC - Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle
6 Centre for Chronic Infectious and Inflammation Disease [Bundoora, VIC, Australie]
2 INTS - Institut National de la Transfusion Sanguine [Paris]
3 Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions
4 Proteomics Core Facility [Lausanne, Suisse]
5 MIVEGEC - Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle
6 Centre for Chronic Infectious and Inflammation Disease [Bundoora, VIC, Australie]
Dominique Dorin-Semblat
- Fonction : Auteur
- PersonId : 921893
Jean-Philippe Semblat
- Fonction : Auteur
- PersonId : 974593
Jose-Juan Lopez-Rubio
- Fonction : Auteur
- PersonId : 171940
- IdHAL : jose-juan-lopez-rubio
- ORCID : 0000-0002-0555-1122
Artur Scherf
- Fonction : Auteur
- PersonId : 758390
- ORCID : 0000-0003-2411-3328
- IdRef : 096696346
Benoît Gamain
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 178226
- IdHAL : benoit-gamain
- ORCID : 0000-0002-8255-2145
- IdRef : 177113782
Connectez-vous pour contacter l'auteur
Résumé
Plasmodium falciparum is the main cause of disease and death from malaria. P. falciparum virulence resides in the ability of infected erythrocytes (IEs) to sequester in various tissues through the interaction between members of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesin family to various host receptors. Here, we investigated the effect of phosphorylation of variant surface antigen 2-CSA (VAR2CSA), a member of the PfEMP1 family associated to placental sequestration, on its capacity to adhere to chondroitin sulfate A (CSA) present on the placental syncytium. We showed that phosphatase treatment of IEs impairs cytoadhesion to CSA. MS analysis of recombinant VAR2CSA phosphosites prior to and after phosphatase treatment, as well as of native VAR2CSA expressed on IEs, identified critical phosphoresidues associated with CSA binding. Site-directed mutagenesis on recombinant VAR2CSA of 3 phosphoresidues localised within the CSA-binding region confirmed in vitro their functional importance. Furthermore, using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9), we generated a parasite line in which the phosphoresidue T934 is changed to alanine and showed that this mutation strongly impairs IEs cytoadhesion to CSA. Taken together, these results demonstrate that phosphorylation of the extracellular region of VAR2CSA plays a major role in IEs cytoadhesion to CSA and provide new molecular insights for strategies aiming to reduce the morbidity and mortality of PM.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Phosphorylation of the VAR2CSA extracellular region is associated with enhanced adhesive properties to the placental receptor CSA
|
Résumé |
en
Plasmodium falciparum is the main cause of disease and death from malaria. P. falciparum virulence resides in the ability of infected erythrocytes (IEs) to sequester in various tissues through the interaction between members of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesin family to various host receptors. Here, we investigated the effect of phosphorylation of variant surface antigen 2-CSA (VAR2CSA), a member of the PfEMP1 family associated to placental sequestration, on its capacity to adhere to chondroitin sulfate A (CSA) present on the placental syncytium. We showed that phosphatase treatment of IEs impairs cytoadhesion to CSA. MS analysis of recombinant VAR2CSA phosphosites prior to and after phosphatase treatment, as well as of native VAR2CSA expressed on IEs, identified critical phosphoresidues associated with CSA binding. Site-directed mutagenesis on recombinant VAR2CSA of 3 phosphoresidues localised within the CSA-binding region confirmed in vitro their functional importance. Furthermore, using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9), we generated a parasite line in which the phosphoresidue T934 is changed to alanine and showed that this mutation strongly impairs IEs cytoadhesion to CSA. Taken together, these results demonstrate that phosphorylation of the extracellular region of VAR2CSA plays a major role in IEs cytoadhesion to CSA and provide new molecular insights for strategies aiming to reduce the morbidity and mortality of PM.
|
Auteur(s) |
Dominique Dorin-Semblat
1, 2
, Marilou Tétard
1, 2
, Aurélie Claës
3
, Jean-Philippe Semblat
1, 2
, Sébastien Dechavanne
1, 2
, Zaineb Fourati
1, 2
, Romain Hamelin
4
, Florence Armand
4
, Graziella Matesic
1, 2
, Sofia Nunes-Silva
1, 2
, Anand Srivastava
1, 2
, Stéphane Gangnard
1, 2
, Jose-Juan Lopez-Rubio
5
, Marc Moniatte
4
, Christian Doerig
6
, Artur Scherf
3
, Benoît Gamain
1, 2
1
BIGR (UMR_S_1134 / U1134) -
Biologie Intégrée du Globule Rouge
( 246987 )
- 6 rue Alexandre Cabanel - 75739 Paris cedex 15
- France
2
INTS -
Institut National de la Transfusion Sanguine [Paris]
( 266750 )
- 6 rue Alexandre Cabanel, 75739 Paris cedex 15
- France
3
Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions
( 462748 )
- Département des Parasites et Insectes vecteurs, 25-28, rue du docteur Roux, 75724 Paris Cedex 15
- France
4
Proteomics Core Facility [Lausanne, Suisse]
( 568068 )
- Suisse
5
MIVEGEC -
Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle
( 166573 )
- 911 Avenue Agropolis BP 64501 34394 Montpellier cedex 5
- France
6
Centre for Chronic Infectious and Inflammation Disease [Bundoora, VIC, Australie]
( 568071 )
- Australie
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2019-06-10
|
Volume |
17
|
Numéro |
6
|
Page/Identifiant |
e3000308
|
Domaine(s) |
|
Financement |
|
Projet(s) ANR |
|
DOI | 10.1371/journal.pbio.3000308 |
Pubmed Id | 31181082 |
PubMed Central | PMC6586358 |
Origine :
Publication financée par une institution
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