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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, <jats:italic>Plasmodium<\/jats:italic> does not have either a TOR complex nor the GCN2-downstream transcription factors. While Ile starvation has been shown to trigger eIF2\u03b1 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 <jats:italic>Plasmodium<\/jats:italic> 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\u2014the last two clustering with the eukaryotic eIF2\u03b1 kinases\u2014as critical for <jats:italic>Plasmodium<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s42003-023-04566-y","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T08:25:35Z","timestamp":1676967935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5537-6812","authenticated-orcid":false,"given":"In\u00eas M.","family":"Marreiros","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1467-1529","authenticated-orcid":false,"given":"Sofia","family":"Marques","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Parreira","sequence":"additional","affiliation":[]},{"given":"Vincent","family":"Mastrodomenico","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1710-5362","authenticated-orcid":false,"given":"Bryan C.","family":"Mounce","sequence":"additional","affiliation":[]},{"given":"Chantal T.","family":"Harris","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0089-1096","authenticated-orcid":false,"given":"Bj\u00f6rn F.","family":"Kafsack","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1716-168X","authenticated-orcid":false,"given":"Oliver","family":"Billker","sequence":"additional","affiliation":[]},{"given":"Vanessa","family":"Zuzarte-Lu\u00eds","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-1041","authenticated-orcid":false,"given":"Maria M.","family":"Mota","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"4566_CR1","unstructured":"WHO. 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