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A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, IL, Maywood, United States.
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2023 (Engelska)Ingår i: Communications Biology, E-ISSN 2399-3642, Vol. 6, nr 1, artikel-id 205Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Eukaryotes have canonical pathways for responding to amino acid (AA) availability. Under AA-limiting conditions, the TOR complex is repressed, whereas the sensor kinase GCN2 is activated. While these pathways have been highly conserved throughout evolution, malaria parasites are a rare exception. Despite auxotrophic for most AA, Plasmodium does not have either a TOR complex nor the GCN2-downstream transcription factors. While Ile starvation has been shown to trigger eIF2α phosphorylation and a hibernation-like response, the overall mechanisms mediating detection and response to AA fluctuation in the absence of such pathways has remained elusive. Here we show that Plasmodium parasites rely on an efficient sensing pathway to respond to AA fluctuations. A phenotypic screen of kinase knockout mutant parasites identified nek4, eIK1 and eIK2—the last two clustering with the eukaryotic eIF2α kinases—as critical for Plasmodium to sense and respond to distinct AA-limiting conditions. Such AA-sensing pathway is temporally regulated at distinct life cycle stages, allowing parasites to actively fine-tune replication and development in response to AA availability. Collectively, our data disclose a set of heterogeneous responses to AA depletion in malaria parasites, mediated by a complex mechanism that is critical for modulating parasite growth and survival.

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Nature Publishing Group, 2023. Vol. 6, nr 1, artikel-id 205
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Cell- och molekylärbiologi
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URN: urn:nbn:se:umu:diva-205509DOI: 10.1038/s42003-023-04566-yISI: 000936156000002PubMedID: 36810637Scopus ID: 2-s2.0-85148710327OAI: oai:DiVA.org:umu-205509DiVA, id: diva2:1743017
Tillgänglig från: 2023-03-13 Skapad: 2023-03-13 Senast uppdaterad: 2023-09-05Bibliografiskt granskad

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Molekylär Infektionsmedicin, Sverige (MIMS)Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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