{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:56:38Z","timestamp":1787313398561,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009696","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T00:00:00Z","timestamp":1625529600000}}],"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["208780\/Z\/17\/Z)"],"award-info":[{"award-number":["208780\/Z\/17\/Z)"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["101842\/Z13\/Z"],"award-info":[{"award-number":["101842\/Z13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"United States Public Health Service","award":["R01 AI035739"],"award-info":[{"award-number":["R01 AI035739"]}]},{"name":"Jacobs School of Medicine and Biomedical Sciences"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Iron is an essential regulatory signal for virulence factors in many pathogens. Mammals and bloodstream form (BSF)\n                    <jats:italic>Trypanosoma brucei<\/jats:italic>\n                    obtain iron by receptor-mediated endocytosis of transferrin bound to receptors (TfR) but the mechanisms by which\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>brucei<\/jats:italic>\n                    subsequently handles iron remains enigmatic. Here, we analyse the transcriptome of\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>brucei<\/jats:italic>\n                    cultured in iron-rich and iron-poor conditions. We show that adaptation to iron-deprivation induces upregulation of TfR, a cohort of parasite-specific genes (ESAG3, PAGS), genes involved in glucose uptake and glycolysis (THT1 and hexokinase), endocytosis (Phosphatidic Acid Phosphatase, PAP2), and most notably a divergent RNA binding protein RBP5, indicative of a non-canonical mechanism for regulating intracellular iron levels. We show that cells depleted of TfR by RNA silencing import free iron as a compensatory survival strategy. The TfR and RBP5 iron response are reversible by genetic complementation, the response kinetics are similar, but the regulatory mechanisms are distinct. Increased TfR protein is due to increased mRNA. Increased RBP5 expression, however, occurs by a post-transcriptional feedback mechanism whereby RBP5 interacts with its own, and with\n                    <jats:italic>PAP2<\/jats:italic>\n                    mRNAs. Further observations suggest that increased RBP5 expression in iron-deprived cells has a maximum threshold as ectopic overexpression above this threshold disrupts normal cell cycle progression resulting in an accumulation of anucleate cells and cells in G2\/M phase. This phenotype is not observed with overexpression of RPB5 containing a point mutation (F61A) in its single RNA Recognition Motif. Our experiments shed new light on how\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>brucei<\/jats:italic>\n                    BSFs reorganise their transcriptome to deal with iron stress revealing the first iron responsive RNA binding protein that is co-regulated with TfR, is important for cell viability and iron homeostasis; two essential processes for successful proliferation.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009696","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T16:04:23Z","timestamp":1624464263000},"page":"e1009696","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["Novel aspects of iron homeostasis in pathogenic bloodstream form Trypanosoma brucei"],"prefix":"10.1371","volume":"17","author":[{"given":"Carla","family":"Gilabert Carbajo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8561-5607","authenticated-orcid":true,"given":"Lucy J.","family":"Cornell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2339-0649","authenticated-orcid":true,"given":"Youssef","family":"Madbouly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4416-0623","authenticated-orcid":true,"given":"Zhihao","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip A.","family":"Yates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0051-017X","authenticated-orcid":true,"given":"Michele","family":"Tinti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3742-6502","authenticated-orcid":true,"given":"Calvin","family":"Tiengwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ppat.1009696.ref001","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.17716","article-title":"The skin is a significant but overlooked anatomical reservoir for vector-borne African trypanosomes","volume":"5","author":"P 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