An essential vesicular-trafficking phospholipase mediates neutral lipid synthesis and contributes to hemozoin formation in Plasmodium falciparum.
Hemozoin
Host-haemoglobin
Malaria
Neutral lipids
Phospholipase
Phospholipid metabolism
Journal
BMC biology
ISSN: 1741-7007
Titre abrégé: BMC Biol
Pays: England
ID NLM: 101190720
Informations de publication
Date de publication:
11 08 2021
11 08 2021
Historique:
received:
20
03
2020
accepted:
30
04
2021
entrez:
12
8
2021
pubmed:
13
8
2021
medline:
21
1
2022
Statut:
epublish
Résumé
Plasmodium falciparum is the pathogen responsible for the most devastating form of human malaria. As it replicates asexually in the erythrocytes of its human host, the parasite feeds on haemoglobin uptaken from these cells. Heme, a toxic by-product of haemoglobin utilization by the parasite, is neutralized into inert hemozoin in the food vacuole of the parasite. Lipid homeostasis and phospholipid metabolism are crucial for this process, as well as for the parasite's survival and propagation within the host. P. falciparum harbours a uniquely large family of phospholipases, which are suggested to play key roles in lipid metabolism and utilization. Here, we show that one of the parasite phospholipase (P. falciparum lysophospholipase, PfLPL1) plays an essential role in lipid homeostasis linked with the haemoglobin degradation and heme conversion pathway. Fluorescence tagging showed that the PfLPL1 in infected blood cells localizes to dynamic vesicular structures that traffic from the host-parasite interface at the parasite periphery, through the cytosol, to get incorporated into a large vesicular lipid rich body next to the food-vacuole. PfLPL1 is shown to harbour enzymatic activity to catabolize phospholipids, and its transient downregulation in the parasite caused a significant reduction of neutral lipids in the food vacuole-associated lipid bodies. This hindered the conversion of heme, originating from host haemoglobin, into the hemozoin, and disrupted the parasite development cycle and parasite growth. Detailed lipidomic analyses of inducible knock-down parasites deciphered the functional role of PfLPL1 in generation of neutral lipid through recycling of phospholipids. Further, exogenous fatty-acids were able to complement downregulation of PfLPL1 to rescue the parasite growth as well as restore hemozoin levels. We found that the transient downregulation of PfLPL1 in the parasite disrupted lipid homeostasis and caused a reduction in neutral lipids essentially required for heme to hemozoin conversion. Our study suggests a crucial link between phospholipid catabolism and generation of neutral lipids (TAGs) with the host haemoglobin degradation pathway.
Sections du résumé
BACKGROUND
Plasmodium falciparum is the pathogen responsible for the most devastating form of human malaria. As it replicates asexually in the erythrocytes of its human host, the parasite feeds on haemoglobin uptaken from these cells. Heme, a toxic by-product of haemoglobin utilization by the parasite, is neutralized into inert hemozoin in the food vacuole of the parasite. Lipid homeostasis and phospholipid metabolism are crucial for this process, as well as for the parasite's survival and propagation within the host. P. falciparum harbours a uniquely large family of phospholipases, which are suggested to play key roles in lipid metabolism and utilization.
RESULTS
Here, we show that one of the parasite phospholipase (P. falciparum lysophospholipase, PfLPL1) plays an essential role in lipid homeostasis linked with the haemoglobin degradation and heme conversion pathway. Fluorescence tagging showed that the PfLPL1 in infected blood cells localizes to dynamic vesicular structures that traffic from the host-parasite interface at the parasite periphery, through the cytosol, to get incorporated into a large vesicular lipid rich body next to the food-vacuole. PfLPL1 is shown to harbour enzymatic activity to catabolize phospholipids, and its transient downregulation in the parasite caused a significant reduction of neutral lipids in the food vacuole-associated lipid bodies. This hindered the conversion of heme, originating from host haemoglobin, into the hemozoin, and disrupted the parasite development cycle and parasite growth. Detailed lipidomic analyses of inducible knock-down parasites deciphered the functional role of PfLPL1 in generation of neutral lipid through recycling of phospholipids. Further, exogenous fatty-acids were able to complement downregulation of PfLPL1 to rescue the parasite growth as well as restore hemozoin levels.
CONCLUSIONS
We found that the transient downregulation of PfLPL1 in the parasite disrupted lipid homeostasis and caused a reduction in neutral lipids essentially required for heme to hemozoin conversion. Our study suggests a crucial link between phospholipid catabolism and generation of neutral lipids (TAGs) with the host haemoglobin degradation pathway.
Identifiants
pubmed: 34380472
doi: 10.1186/s12915-021-01042-z
pii: 10.1186/s12915-021-01042-z
pmc: PMC8359613
doi:
Substances chimiques
Hemeproteins
0
Phospholipids
0
hemozoin
39404-00-7
Heme
42VZT0U6YR
Phospholipases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
159Informations de copyright
© 2021. The Author(s).
Références
N Engl J Med. 2017 Mar 9;376(10):991-3
pubmed: 28225668
J Immunol Methods. 1997 Mar 28;202(2):133-41
pubmed: 9107302
Parasitology. 2006 Oct;133(Pt 4):399-410
pubmed: 16780611
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5392-7
pubmed: 23471987
Cell Rep. 2020 Mar 17;30(11):3778-3792.e9
pubmed: 32187549
Mol Biochem Parasitol. 2004 Jun;135(2):197-209
pubmed: 15110461
Parasitol Int. 2000 Sep;49(3):219-29
pubmed: 11426577
Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4411-6
pubmed: 21368162
Mol Biochem Parasitol. 2007 Nov;156(1):12-23
pubmed: 17698213
Biochim Biophys Acta. 1991 Mar 18;1063(1):45-50
pubmed: 2015260
Cell Host Microbe. 2008 Dec 11;4(6):567-78
pubmed: 19064257
Nat Methods. 2007 Dec;4(12):1007-9
pubmed: 17994030
Trop Med Int Health. 2008 Sep;13(9):1111-30
pubmed: 18657092
Parasitology. 2007 Nov;134(Pt 12):1671-7
pubmed: 17610764
Biochem J. 2007 Feb 15;402(1):197-204
pubmed: 17044814
J Biol Chem. 2004 Oct 8;279(41):43000-7
pubmed: 15304495
mBio. 2016 Oct 18;7(5):
pubmed: 27795395
Infect Immun. 2002 Jul;70(7):3939-43
pubmed: 12065539
J Biol Chem. 2016 Nov 11;291(46):24280-24292
pubmed: 27694132
Mol Biol Evol. 2004 Nov;21(11):2161-71
pubmed: 15306658
Exp Parasitol. 2005 Jan;109(1):7-15
pubmed: 15639134
PLoS One. 2008 Mar 05;3(3):e1732
pubmed: 18320051
J Lipid Res. 2018 Aug;59(8):1461-1471
pubmed: 29853527
J Biol Chem. 2004 Mar 5;279(10):9222-32
pubmed: 14668349
Cell Host Microbe. 2015 Sep 9;18(3):371-81
pubmed: 26355219
Eukaryot Cell. 2003 Oct;2(5):1128-31
pubmed: 14555495
Biochem J. 2001 Apr 15;355(Pt 2):333-8
pubmed: 11284719
Mol Biochem Parasitol. 2010 Oct;173(2):69-80
pubmed: 20478340
Cell. 2017 Dec 14;171(7):1532-1544.e15
pubmed: 29129376
Cell Microbiol. 2017 Jan;19(1):
pubmed: 27324409
Cell Mol Life Sci. 2006 Jun;63(12):1355-69
pubmed: 16649142
Malar J. 2012 Oct 08;11:337
pubmed: 23043460
Biochim Biophys Acta. 2015 Mar;1853(3):699-710
pubmed: 25573429
Nat Protoc. 2011 Aug 25;6(9):1412-28
pubmed: 21886105
Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7506-11
pubmed: 23589867
Mol Biochem Parasitol. 2012 Nov;186(1):29-37
pubmed: 23000576
Anal Biochem. 2004 Feb 1;325(1):85-91
pubmed: 14715288
Neurochem Pathol. 1987 Oct;7(2):99-128
pubmed: 3328838
Clin Biochem. 2002 Jul;35(5):411-6
pubmed: 12270773
J Biol Chem. 2005 Feb 25;280(8):6752-60
pubmed: 15590623
PLoS Pathog. 2009 Jan;5(1):e1000270
pubmed: 19165333
Biochem Biophys Res Commun. 2003 Sep 5;308(4):736-43
pubmed: 12927780
J Biol Chem. 2005 Jan 14;280(2):1432-7
pubmed: 15513918
Biochim Biophys Acta. 2015 Nov;1853(11 Pt A):2856-69
pubmed: 26284889
Int J Med Microbiol. 2018 Jan;308(1):129-141
pubmed: 28988696
Lancet Infect Dis. 2007 Oct;7(10):675-85
pubmed: 17897610
PLoS Pathog. 2016 Aug 04;12(8):e1005765
pubmed: 27490259
J Biol Chem. 2014 Mar 7;289(10):6809-6824
pubmed: 24429285
Malar J. 2017 Feb 16;16(1):79
pubmed: 28202027
Microbes Infect. 2003 May;5(6):545-52
pubmed: 12758284
Nature. 2002 Oct 3;419(6906):498-511
pubmed: 12368864
J Biol Chem. 2008 Mar 21;283(12):7894-900
pubmed: 18178564
Biochemistry. 2010 Nov 30;49(47):10107-16
pubmed: 20979358
J Biol Chem. 2013 Nov 1;288(44):31971-83
pubmed: 24043620
Cell Host Microbe. 2016 Mar 9;19(3):349-60
pubmed: 26962945
J Histochem Cytochem. 1985 Aug;33(8):833-6
pubmed: 4020099
Antimicrob Agents Chemother. 2007 Feb;51(2):651-6
pubmed: 17116669
J Protozool. 1990 Nov-Dec;37(6):465-70
pubmed: 2086778
Mol Biochem Parasitol. 2003 Feb;126(2):143-54
pubmed: 12615313
Cell Microbiol. 2009 Mar;11(3):506-20
pubmed: 19068099
Exp Parasitol. 2011 Sep;129(1):75-80
pubmed: 21651909
Cell Microbiol. 2013 Oct;15(10):1660-73
pubmed: 23521916
Science. 2010 May 14;328(5980):910-2
pubmed: 20466936
J Cell Sci. 2004 Mar 15;117(Pt 8):1469-80
pubmed: 15020675
Methods Mol Biol. 2004;270:263-76
pubmed: 15153633
Mol Microbiol. 2004 Oct;54(1):109-22
pubmed: 15458409
Biochem J. 1999 Oct 1;343 Pt 1:177-83
pubmed: 10493927