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Two Plasmodium 6‐Cys family‐related proteins have distinct and critical roles in liver‐stage development
Author(s) -
Annoura Takeshi,
Schaijk Ben C. L.,
Ploemen Ivo H. J.,
Sajid Mohammed,
Lin Jingwen,
Vos Martijn W.,
Dinmohamed Avinash G.,
Inaoka Daniel K.,
Rijpma Sanna R.,
Gemert GeertJan,
ChevalleyMaurel Severine,
Kiełbasa Szymon M.,
Scheltinga Fay,
FrankeFayard Blandine,
Klop Onny,
Hermsen Cornelus C.,
Kita Kiyoshi,
Gego Audrey,
Franetich JeanFrancois,
Mazier Dominique,
Hoffman Stephen L.,
Janse Chris J.,
Sauerwein Robert W.,
Khan Shahid M.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-241570
Subject(s) - biology , plasmodium berghei , mutant , microbiology and biotechnology , plasmodium falciparum , hepatocyte , cysteine , gene , genetics , immunology , malaria , in vitro , biochemistry , enzyme
The 10 Plasmodium 6‐Cys proteins have critical roles throughout parasite development and are targets for antimalaria vaccination strategies. We analyzed the conserved 6‐cysteine domain of this family and show that only the last 4 positionally conserved cysteine residues are diagnostic for this domain and identified 4 additional “6‐Cys family‐related” proteins. Two of these, sequestrin and B9, are critical to Plasmodium liver‐stage development. RT‐PCR and immunofluorescence assays show that B9 is translationally repressed in sporozoites and is expressed after hepatocyte invasion where it localizes to the parasite plasma membrane. Mutants lacking B9 expression in the rodent malaria parasites P. berghei and P. yoelii and the human parasite P. falciparum developmentally arrest in hepatocytes. P. berghei mutants arrest in the livers of BALB/c (100%) and C57BL6 mice (>99.9%), and in cultures of Huh7 human‐hepatoma cell line. Similarly, P. falciparum mutants while fully infectious to primary human hepatocytes abort development 3 d after infection. This growth arrest is associated with a compromised parasitophorous vacuole membrane a phenotype similar to, but distinct from, mutants lacking the 6‐Cys sporozoite proteins P52 and P36. Our results show that 6‐Cys proteins have critical but distinct roles in establishment and maintenance of a parasitophorous vacuole and subsequent liver‐stage development—Annoura, T., van Schaijk, B. C. L., Ploemen, I. H. J., Sajid, M., Lin, J.‐W., Vos, M. W., Dinmohamed, A G., Inaoka, D. K., Rijpma, S. R., van Gemert, G.‐J., Chevalley‐Maurel, S., Kiełbasa, S. M., Scheltinga, F., Franke‐Fayard, B., Klop, O. Hermsen, C. C., Kita, K., Gego, A., Franetich, J.‐F., Mazier, D., Hoffman, S. L., Janse, C. J., Sauerwein, R. W., Khan, S. M. Two Plasmodium 6‐Cys family‐related proteins have distinct and critical roles in liver‐stage development. FASEB J . 28, 2158–2170 (2014). www.fasebj.org