PMID- 37249423
OWN - NLM
STAT- MEDLINE
DCOM- 20230619
LR  - 20240114
IS  - 2165-0497 (Electronic)
IS  - 2165-0497 (Linking)
VI  - 11
IP  - 3
DP  - 2023 Jun 15
TI  - Plasmodium falciparum GAP40 Plays an Essential Role in Merozoite Invasion and 
      Gametocytogenesis.
PG  - e0143423
LID - 10.1128/spectrum.01434-23 [doi]
LID - e01434-23
AB  - Cyclic invasion of red blood cells (RBCs) by Plasmodium merozoites is associated 
      with the symptoms and pathology of malaria. Merozoite invasion is powered 
      actively and rapidly by a parasite actomyosin motor called the glideosome. The 
      ability of the glideosome to generate force to support merozoite entry into the 
      host RBCs is thought to rely on its stable anchoring within the inner membrane 
      complex (IMC) through membrane-resident proteins, such as GAP50 and GAP40. Using 
      a conditional knockdown (KD) approach, we determined that PfGAP40 was required 
      for asexual blood-stage replication. PfGAP40 is not needed for merozoite egress 
      from host RBCs or for the attachment of merozoites to new RBCs. PfGAP40 
      coprecipitates with PfGAP45 and PfGAP50. During merozoite invasion, PfGAP40 is 
      associated strongly with stabilizing the expression levels of PfGAP45 and PfGAP50 
      in the schizont stage. Although PfGAP40 KD did not influence IMC integrity, it 
      impaired the maturation of gametocytes. In addition, PfGAP40 is phosphorylated, 
      and mutations that block phosphorylation of PfGAP40 at the C-terminal serine 
      residues S370, S372, S376, S405, S409, S420, and S445 reduced merozoite invasion 
      efficiency. Overall, our findings implicate PfGAP40 as an important regulator for 
      the gliding activity of merozoites and suggest that phosphorylation is required 
      for PfGAP40 function. IMPORTANCE Red blood cell invasion is central to the 
      pathogenesis of the malaria parasite, and the parasite proteins involved in this 
      process are potential therapeutic targets. Gliding motility powers merozoite 
      invasion and is driven by a unique molecular motor termed the glideosome. The 
      glideosome is stably anchored to the parasite inner membrane complex (IMC) 
      through membrane-resident proteins. In the present study, we demonstrate the 
      importance of an IMC-resident glideosome component, PfGAP40, that plays a 
      critical role in stabilizing the expression levels of glideosome components in 
      the schizont stage. We determined that phosphorylation of PfGAP40 at C-terminal 
      residues is required for efficient merozoite invasion.
FAU - He, Lu
AU  - He L
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Qiu, Yue
AU  - Qiu Y
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
AD  - Department of Cardiovascular Ultrasound, The First Hospital of China Medical 
      University, Shenyang, Liaoning, China.
FAU - Pang, Geping
AU  - Pang G
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Li, Siqi
AU  - Li S
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Wang, Jingjing
AU  - Wang J
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Feng, Yonghui
AU  - Feng Y
AD  - Department of Laboratory Medicine, the First Hospital of China Medical 
      University, Shenyang, Liaoning, China.
AD  - National Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, 
      China.
FAU - Chen, Lumeng
AU  - Chen L
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Zhu, Liying
AU  - Zhu L
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Liu, Yinjie
AU  - Liu Y
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Cui, Liwang
AU  - Cui L
AUID- ORCID: 0000-0002-8338-1974
AD  - College of Public Health, University of South Florida, Tampa, Florida, USA.
FAU - Cao, Yaming
AU  - Cao Y
AUID- ORCID: 0000-0001-5315-1636
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
FAU - Zhu, Xiaotong
AU  - Zhu X
AUID- ORCID: 0000-0002-9064-586X
AD  - Department of Immunology, College of Basic Medical Sciences, China Medical 
      University, Shenyang, Liaoning, China.
LA  - eng
GR  - R01 AI150533/AI/NIAID NIH HHS/United States
GR  - U19 AI089672/AI/NIAID NIH HHS/United States
GR  - R01 AI128940/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230530
PL  - United States
TA  - Microbiol Spectr
JT  - Microbiology spectrum
JID - 101634614
RN  - 0 (Protozoan Proteins)
RN  - 0 (Membrane Proteins)
SB  - IM
MH  - Animals
MH  - *Plasmodium falciparum/genetics/metabolism
MH  - Merozoites/metabolism
MH  - Protozoan Proteins/metabolism
MH  - Membrane Proteins/metabolism
MH  - *Malaria/parasitology
PMC - PMC10269477
OTO - NOTNLM
OT  - GAP40
OT  - Plasmodium falciparum
OT  - glideosome
OT  - invasion
OT  - phosphorylation
COIS- The authors declare no conflict of interest.
EDAT- 2023/05/30 13:07
MHDA- 2023/06/19 13:08
PMCR- 2023/05/30
CRDT- 2023/05/30 10:03
PHST- 2023/06/19 13:08 [medline]
PHST- 2023/05/30 13:07 [pubmed]
PHST- 2023/05/30 10:03 [entrez]
PHST- 2023/05/30 00:00 [pmc-release]
AID - 01434-23 [pii]
AID - spectrum.01434-23 [pii]
AID - 10.1128/spectrum.01434-23 [doi]
PST - ppublish
SO  - Microbiol Spectr. 2023 Jun 15;11(3):e0143423. doi: 10.1128/spectrum.01434-23. 
      Epub 2023 May 30.