Plasmodium falciparum Acetyl-CoA Synthetase Is Essential for Parasite Intraerythrocytic Development and Chromatin Modification

Autor(es)

Prata, Isadora Oliveira ^[1] ; Galindo Cubillos, Eliana Fernanda ^[1] ; Kruger, Arne ^[1] ; Barbosa, Deibs ^[2] ; Martins, Joaquim ^[2] ; Setubal, Joao Carlos ^[2] ; Wunderlich, Gerhard ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508000 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACS INFECTIOUS DISEASES; v. 7, n. 12, p. 3224-3240, DEC 10 2021.
• Citações Web of Science: 0

Resumo

The malaria parasite Plasmodium falciparum possesses a unique Acetyl-CoA Synthetase (PfACS), which provides acetyl moieties for different metabolic and regulatory cellular pathways. We characterized PfACS and studied its role focusing on epigenetic modifications using the var gene family as reporter genes. For this, mutant lines to modulate plasmodial ACS expression by degronmediated protein degradation and ribozyme-induced transcript decay were created. Additionally, an inhibitor of the human Acetyl-CoA Synthetase 2 was tested for its effectiveness in interfering with PfACS. The knockdown of PfACS or its inhibition resulted in impaired parasite growth. Decreased levels of PfACS also led to differential histone acetylation patterns, altered variant gene expression, and concomitantly decreased cytoadherence of infected red blood cells containing knocked-down parasites. Further, ChIP analysis revealed the presence of PfACS in many loci in ring stage parasites, underscoring its involvement in the regulation of chromatin. Due to its central function in the plasmodial metabolism and significant differences to human ACS, PfACS is an interesting target for drug development. (AU)

• Processo FAPESP: 17/24267-7 - Papel de modificadores de cromatina na dinâmica da transcrição de fatores de virulência no parasita da Malária Plasmodium falciparum
• Beneficiário: Gerhard Wunderlich
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/12659-5 - O papel de três fatores de transcrição ApiAP2 no controle na transcrição no ciclo intraeritrocítico e sexual de Plasmodium falciparum
• Beneficiário: Eliana Fernanda Galindo Cubillos
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/08820-0 - Inibidores da via de síntese de vitamina B6 entregues por associação com nanopartículas contra Plasmodium sp
• Beneficiário: Arne Kruger
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/26722-8 - Drug discovery contra doenças infecciosas humanos
• Beneficiário: Carsten Wrenger
• Modalidade de apoio: Auxílio à Pesquisa - Temático