A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation

被引:146
作者
Klemba, M
Gluzman, I
Goldberg, DE
机构
[1] Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Microbiol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Howard Hughes Med Inst, Dept Med, St Louis, MO 63110 USA
关键词
D O I
10.1074/jbc.M408123200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Intraerythrocytic growth of the human malaria parasite Plasmodium falciparum requires the catabolism of large amounts of host cell hemoglobin. Endoproteolytic digestion of hemoglobin to short oligopeptides occurs in an acidic organelle called the food vacuole. How amino acids are generated from these peptides is not well understood. To gain insight into this process, we have studied a plasmodial ortholog of the lysosomal exopeptidase cathepsin C. The plasmodial enzyme dipeptidyl aminopeptidase 1 (DPAP1) was enriched from parasite extract by two different approaches and was shown to possess hydrolytic activity against fluorogenic dipeptide substrates. To localize DPAP1 we created a transgenic parasite line expressing a chromosomally encoded DPAP1-green fluorescent protein fusion. Green fluorescent protein fluorescence was observed in the food vacuole of live transgenic parasites, and anti-DPAP1 antibody labeled the food vacuole in parasite cryosections. Together these data implicate DPAP1 in the generation of dipeptides from hemoglobin-derived oligopeptides. To assess the significance of DPAP1, we attempted to ablate DPAP1 activity from blood stage parasites by truncating the chromosomal DPAP1-coding sequence. The inability to disrupt the coding sequence indicates that DPAP1 is important for asexual proliferation. The proenzyme form of DPAP1 was found to accumulate in the parasitophorous vacuole of mature parasites. This observation suggests a trafficking route for DPAP1 through the parasitophorous vacuole to the food vacuole.
引用
收藏
页码:43000 / 43007
页数:8
相关论文
共 62 条
[1]   Complete genome sequence of the apicomplexan, Cryptosporidium parvum [J].
Abrahamsen, MS ;
Templeton, TJ ;
Enomoto, S ;
Abrahante, JE ;
Zhu, G ;
Lancto, CA ;
Deng, MQ ;
Liu, C ;
Widmer, G ;
Tzipori, S ;
Buck, GA ;
Xu, P ;
Bankier, AT ;
Dear, PH ;
Konfortov, BA ;
Spriggs, HF ;
Iyer, L ;
Anantharaman, V ;
Aravind, L ;
Kapur, V .
SCIENCE, 2004, 304 (5669) :441-445
[2]   The signal sequence of exported protein-1 directs the green fluorescent protein to the parasitophorous vacuole of transfected malaria parasites [J].
Adisa, A ;
Rug, M ;
Klonis, N ;
Foley, M ;
Cowman, AF ;
Tilley, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (08) :6532-6542
[3]   Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis [J].
Adkison, AM ;
Raptis, SZ ;
Kelley, DG ;
Pham, CTN .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (03) :363-371
[4]   FEEDING MECHANISM OF AVIAN MALARIAL PARASITES [J].
AIKAWA, M ;
HEPLER, PK ;
HUFF, CG ;
SPRINZ, H .
JOURNAL OF CELL BIOLOGY, 1966, 28 (02) :355-+
[5]   Properties, stage-dependent expression and localization of Plasmodium falciprum M1 family zinc-aminopeptidase [J].
Allary, M ;
Schrevel, J ;
Florent, I .
PARASITOLOGY, 2002, 125 :1-10
[6]   Protein sorting in Plasmodium falciparum-infected red blood cells permeabilized with the pore-forming protein streptolysin O [J].
Ansorge, I ;
Benting, J ;
Bhakdi, S ;
Lingelbach, K .
BIOCHEMICAL JOURNAL, 1996, 315 :307-314
[7]   Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine [J].
Banerjee, R ;
Liu, J ;
Beatty, W ;
Pelosof, L ;
Klemba, M ;
Goldberg, DE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (02) :990-995
[8]   Drug resistance-associated pfCRT mutations confer decreased Plasmodium falciparum digestive vacuolar pH [J].
Bennett, TN ;
Kosar, AD ;
Ursos, LMB ;
Dzekunov, S ;
Sidhu, ABS ;
Fidock, DA ;
Roepe, PD .
MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 2004, 133 (01) :99-114
[9]   BREFELDIN-A INHIBITS TRANSPORT OF THE GLYCOPHORIN-BINDING PROTEIN FROM PLASMODIUM-FALCIPARUM INTO THE HOST ERYTHROCYTE [J].
BENTING, J ;
MATTEI, D ;
LINGELBACH, K .
BIOCHEMICAL JOURNAL, 1994, 300 :821-826
[10]   The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum [J].
Bozdech, Z ;
Llinás, M ;
Pulliam, BL ;
Wong, ED ;
Zhu, JC ;
DeRisi, JL .
PLOS BIOLOGY, 2003, 1 (01) :85-100