Article (Scientific journals)
INPP5K controls the dynamic structure and signaling of wild type and mutated, leukemia-associated IL7 receptors
Moes, Bastien; Li, Hua; Molina Ortiz, Patricia et al.
2023In Blood, 141, p. 1708-1717
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Keywords :
Interleukin-7, receptor, phosphoinositide, 5-phosphatase, inpp5k, leukemia,; interleukin-7 receptor
Abstract :
[en] Signaling downstream of the IL7 receptor plays important physiological and pathological roles, including differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain of function mutations in the IL7Rα chain, the specific component of the receptor for IL7, result in constitutive, IL7-independent signaling and trigger acute lymphoblastic leukemia. Here, we show that loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate PtdIns(4,5)P2 and causes altered dynamic structure of the IL7 receptor. We discovered that the IL7Rα chain contains a very conserved positively-charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region; this region establishes stronger ionic interactions with negatively-charged PtdIns(4,5)P2 in the absence of INPP5K, freezing IL7Rα chain structure. This dynamic structural alteration causes defects in IL7 receptor signaling, culminating in decreased expression of EBF1 and PAX5 transcription factor, in microdomain formation, cytoskeletal reorganization and bone marrow B cell differentiation. Similar alterations following reduced INPP5K expression also impacted mutated, constitutively activated IL7Rα chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyses plasma membrane PtdIns(4,5)P2, allowing the requisite conformational changes of the IL7Rα chain for optimal signaling.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Moes, Bastien ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Functional Genetics
Li, Hua
Molina Ortiz, Patricia ;  Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-R : Labo de génétique fonctionnelle
Radermecker, Coraline ;  Université de Liège - ULiège > GIGA > GIGA I3 - Immunophysiology
Rosu, Adeline ;  Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Vande Catsyne, Charles-Andrew ;  Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-R : Labo de génétique fonctionnelle
Sayyed, Sufyan Ali ;  Université de Liège - ULiège > Unités de recherche interfacultaires > GIGA-R : Labo de génétique fonctionnelle
Fontela Joao
Duque, Mafalda
Mostafa, Alice ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Functional Genetics
Azzi, Abdelhalim ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Functional Genetics
Barata Joao T.
Merino Ramon
Xu, Chenqi
Desmet, Christophe  ;  Université de Liège - ULiège > GIGA > GIGA I3 - Cellular and Molecular Immunology
Schurmans, Stéphane  ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Functional Genetics
More authors (6 more) Less
Language :
English
Title :
INPP5K controls the dynamic structure and signaling of wild type and mutated, leukemia-associated IL7 receptors
Publication date :
2023
Journal title :
Blood
ISSN :
0006-4971
eISSN :
1528-0020
Publisher :
American Society of Hematology, Washington, United States - District of Columbia
Volume :
141
Pages :
1708-1717
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 20 March 2023

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