Delayed death in the malaria parasite Plasmodium falciparum is caused by disruption of prenylation-dependent intracellular trafficking.
Animals
Antimalarials
/ pharmacology
Apicoplasts
/ metabolism
Cell Death
/ drug effects
Hemiterpenes
/ metabolism
Humans
Intracellular Space
/ drug effects
Malaria, Falciparum
/ parasitology
Metabolomics
/ methods
Organophosphorus Compounds
/ metabolism
Plasmodium falciparum
/ drug effects
Protein Prenylation
/ drug effects
Protein Transport
/ drug effects
Protozoan Proteins
/ metabolism
Vacuoles
/ drug effects
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
07
04
2019
accepted:
01
07
2019
revised:
30
07
2019
pubmed:
19
7
2019
medline:
25
1
2020
entrez:
19
7
2019
Statut:
epublish
Résumé
Apicomplexan parasites possess a plastid organelle called the apicoplast. Inhibitors that selectively target apicoplast housekeeping functions, including DNA replication and protein translation, are lethal for the parasite, and several (doxycycline, clindamycin, and azithromycin) are in clinical use as antimalarials. A major limitation of such drugs is that treated parasites only arrest one intraerythrocytic development cycle (approximately 48 hours) after treatment commences, a phenotype known as the 'delayed death' effect. The molecular basis of delayed death is a long-standing mystery in parasitology, and establishing the mechanism would aid rational clinical implementation of apicoplast-targeted drugs. Parasites undergoing delayed death transmit defective apicoplasts to their daughter cells and cannot produce the sole, blood-stage essential metabolic product of the apicoplast: the isoprenoid precursor isopentenyl-pyrophosphate. How the isoprenoid precursor depletion kills the parasite remains unknown. We investigated the requirements for the range of isoprenoids in the human malaria parasite Plasmodium falciparum and characterised the molecular and morphological phenotype of parasites experiencing delayed death. Metabolomic profiling reveals disruption of digestive vacuole function in the absence of apicoplast derived isoprenoids. Three-dimensional electron microscopy reveals digestive vacuole fragmentation and the accumulation of cytostomal invaginations, characteristics common in digestive vacuole disruption. We show that digestive vacuole disruption results from a defect in the trafficking of vesicles to the digestive vacuole. The loss of prenylation of vesicular trafficking proteins abrogates their membrane attachment and function and prevents the parasite from feeding. Our data show that the proximate cause of delayed death is an interruption of protein prenylation and consequent cellular trafficking defects.
Identifiants
pubmed: 31318858
doi: 10.1371/journal.pbio.3000376
pii: PBIOLOGY-D-19-00985
pmc: PMC6667170
doi:
Substances chimiques
Antimalarials
0
Hemiterpenes
0
Organophosphorus Compounds
0
Protozoan Proteins
0
isopentenyl pyrophosphate
358-71-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000376Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Nature. 1997 Nov 27;390(6658):407-9
pubmed: 9389481
PLoS Biol. 2011 Aug;9(8):e1001138
pubmed: 21912516
Antimicrob Agents Chemother. 2018 May 25;62(6):
pubmed: 29555632
Curr Biol. 2004 Jul 13;14(13):R514-6
pubmed: 15242632
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8840-5
pubmed: 16731623
Antimicrob Agents Chemother. 1992 May;36(5):1091-6
pubmed: 1510399
Science. 1999 Sep 3;285(5433):1573-6
pubmed: 10477522
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2463-8
pubmed: 18263733
Sci Rep. 2016 Dec 07;6:38615
pubmed: 27924931
J Biol Chem. 2006 Feb 24;281(8):5197-208
pubmed: 16321976
Methods Enzymol. 2012;506:81-92
pubmed: 22341220
Nat Methods. 2017 Apr;14(4):450-456
pubmed: 28288121
Mol Biol Evol. 2001 Mar;18(3):418-26
pubmed: 11230543
Am J Physiol Cell Physiol. 2001 Jun;280(6):C1576-87
pubmed: 11350753
Mol Microbiol. 2002 Mar;43(5):1309-18
pubmed: 11918815
EMBO J. 2001 Feb 1;20(3):330-9
pubmed: 11157740
Mol Biochem Parasitol. 2002 Feb;119(2):249-56
pubmed: 11814576
J Exp Med. 2011 Jul 4;208(7):1547-59
pubmed: 21690250
Eukaryot Cell. 2006 May;5(5):849-60
pubmed: 16682462
Biophys J. 2010 Aug 4;99(3):953-60
pubmed: 20682274
Antimicrob Agents Chemother. 1994 Jan;38(1):31-7
pubmed: 8141576
Sci Transl Med. 2010 Jul 14;2(40):40ra49
pubmed: 20630856
Int J Parasitol. 2012 Feb;42(2):177-86
pubmed: 22222968
J Infect Dis. 2016 Jan 15;213(2):276-86
pubmed: 26150544
Biochem Pharmacol. 1986 Jul 15;35(14):2435-42
pubmed: 3524576
PLoS Comput Biol. 2009 Apr;5(4):e1000339
pubmed: 19343220
Antimicrob Agents Chemother. 2019 Jan 29;63(2):
pubmed: 30455243
PLoS Pathog. 2009 Jan;5(1):e1000270
pubmed: 19165333
J Struct Biol. 2012 Feb;177(2):224-32
pubmed: 21945653
J Cell Sci. 2010 Feb 1;123(Pt 3):441-50
pubmed: 20067995
Blood. 2003 May 15;101(10):4189-94
pubmed: 12531811
Cell Host Microbe. 2019 Jan 9;25(1):166-173.e5
pubmed: 30581113
Mol Cell Proteomics. 2017 Apr;16(4 suppl 1):S54-S64
pubmed: 28040698
Sci Rep. 2016 Nov 22;6:37502
pubmed: 27874068
Trends Parasitol. 2016 Dec;32(12):953-965
pubmed: 27793563
PLoS Pathog. 2013 Mar;9(3):e1003213
pubmed: 23505371
J Med Chem. 2005 Jun 2;48(11):3704-13
pubmed: 15916422
Sci Rep. 2016 Jun 09;6:27531
pubmed: 27277538
Antimicrob Agents Chemother. 2006 Sep;50(9):3124-31
pubmed: 16940111
Nat Rev Microbiol. 2004 Mar;2(3):203-16
pubmed: 15083156
Antimicrob Agents Chemother. 2001 Sep;45(9):2553-8
pubmed: 11502528
Eukaryot Cell. 2014 Nov;13(11):1348-59
pubmed: 25217461
Nat Commun. 2018 Sep 18;9(1):3801
pubmed: 30228310
Cell. 2017 Jul 13;170(2):260-272.e8
pubmed: 28708996
Nature. 2007 Mar 1;446(7131):88-91
pubmed: 17330044
Antimicrob Agents Chemother. 2004 May;48(5):1803-6
pubmed: 15105138
Science. 2018 May 4;360(6388):
pubmed: 29724925
Physiol Rev. 2001 Apr;81(2):495-537
pubmed: 11274338
Antimicrob Agents Chemother. 2007 Oct;51(10):3485-90
pubmed: 17698630
Eukaryot Cell. 2013 Feb;12(2):215-23
pubmed: 23223036
Am J Trop Med Hyg. 1971 Nov;20(6):811-5
pubmed: 4943475
Nucleic Acids Res. 2016 Jan 4;44(D1):D463-70
pubmed: 26467476
Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25
pubmed: 19603039
Microbiology. 2000 Feb;146 ( Pt 2):315-321
pubmed: 10708370
Antimicrob Agents Chemother. 1995 Jul;39(7):1530-7
pubmed: 7492099
J Biol Chem. 2002 Nov 1;277(44):42066-73
pubmed: 12194969
Antimicrob Agents Chemother. 2017 Dec 21;62(1):
pubmed: 29109165
Traffic. 2008 Aug;9(8):1316-26
pubmed: 18489703
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Biochemistry. 2011 May 3;50(17):3570-7
pubmed: 21438569
J Struct Biol. 1996 Jan-Feb;116(1):71-6
pubmed: 8742726
J Biol Chem. 2013 Dec 20;288(51):36338-50
pubmed: 24163372
Science. 1976 Aug 20;193(4254):673-5
pubmed: 781840
Mol Biochem Parasitol. 2007 Apr;152(2):181-91
pubmed: 17289168
Nat Commun. 2017 Jun 08;8:15710
pubmed: 28593938
Drug Resist Updat. 2001 Jun;4(3):145-51
pubmed: 11768328