PMID- 36711954
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231018
DP  - 2023 May 9
TI  - Plasmodium falciparum GCN5 plays a key role in regulating artemisinin 
      resistance-related stress responses.
LID - 2023.01.11.523703 [pii]
LID - 10.1101/2023.01.11.523703 [doi]
AB  - Plasmodium falciparum causes the most severe malaria and is exposed to various 
      environmental and physiological stresses in the human host. Given that GCN5 plays 
      a critical role in regulating stress responses in model organisms, we aimed to 
      elucidate PfGCN5's function in stress responses in P. falciparum . The protein 
      level of PfGCN5 was substantially induced under three stress conditions (heat 
      shock, low glucose starvation, and dihydroartemisinin, the active metabolite of 
      artemisinin (ART)). With a TetR-DOZI conditional knockdown (KD) system, we 
      successfully down-regulated PfGCN5 to  approximately 50% and found that KD parasites became 
      more sensitive to all three stress conditions. Transcriptomic analysis via 
      RNA-seq identified  approximately 1,000 up-and down-regulated genes in the wildtype (WT) and KD 
      parasites under these stress conditions. Importantly, DHA induced transcriptional 
      alteration of many genes involved in many aspects of stress responses, which were 
      heavily shared among the altered genes under heat shock and low glucose 
      conditions, including ART-resistance-related genes such as K13 and coronin . 
      Based on the expression pattern between WT and KD parasites under three stress 
      conditions,  approximately 300-400 genes were identified to be involved in PfGCN5-dependent, 
      general and stress-condition-specific responses with high levels of overlaps 
      among three stress conditions. Notably, using ring-stage survival assay (RSA), we 
      found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites 
      to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating 
      general and ART-resistance-related stress responses in malaria parasites, 
      implicating PfGCN5 as a potential target for malaria intervention. IMPORTANCE: 
      Malaria leads to about half a million deaths annually and these casualties were 
      majorly caused by the infection of Plasmodium falciparum . This parasite strives 
      to survive by defending against a variety of stress conditions, such as malaria 
      cyclical fever (heat shock), starvation due to low blood sugar (glucose) levels 
      (hypoglycemia), and drug treatment. Previous studies have revealed that P. 
      falciparum has developed unique stress responses to different stresses including 
      ART treatment, and ART-resistant parasites harbor elevated stress responses. In 
      this study, we provide critical evidence on the role of PfGCN5, a histone 
      modifier, and a chromatin coactivator, in regulating general and stress-specific 
      responses in malaria parasites, indicating that PfGCN5 can be used as a potential 
      target for anti-malaria intervention.
FAU - Lucky, Amuza Byaruhanga
AU  - Lucky AB
FAU - Wang, Chengqi
AU  - Wang C
FAU - Shakri, Ahmad Rushdi
AU  - Shakri AR
FAU - Kalamuddin, Mohammad
AU  - Kalamuddin M
FAU - Chim-Ong, Anongruk
AU  - Chim-Ong A
FAU - Li, Xiaolian
AU  - Li X
FAU - Miao, Jun
AU  - Miao J
AUID- ORCID: 0000-0001-9374-6749
LA  - eng
PT  - Preprint
DEP - 20230509
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
UIN - Antimicrob Agents Chemother. 2023 Sep 13;:e0057723. PMID: 37702516
PMC - PMC9882135
EDAT- 2023/01/31 06:00
MHDA- 2023/01/31 06:01
PMCR- 2023/05/15
CRDT- 2023/01/30 03:57
PHST- 2023/01/31 06:00 [pubmed]
PHST- 2023/01/31 06:01 [medline]
PHST- 2023/01/30 03:57 [entrez]
PHST- 2023/05/15 00:00 [pmc-release]
AID - 2023.01.11.523703 [pii]
AID - 10.1101/2023.01.11.523703 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 May 9:2023.01.11.523703. doi: 10.1101/2023.01.11.523703.