INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors

• Author(s): Moës, Bastien ; Li, Hua ; Molina-Ortiz, Patricia ; Radermecker, Coraline ; Rosu, Adeline ; Vande Catsyne, Charles-Andrew ; Sayyed, Sufyan Ali ; Fontela, João ; Duque, Mafalda ; Mostafa, Alice ; Azzi, Abdelhalim ; Barata, João T. ; Merino, Ramon ; Xu, Chenqi ; Desmet, Christophe J. ; Schurmans, Stéphane
• Date: 2023
• Persistent ID: http://hdl.handle.net/10451/57105
• Origin: Repositório da Universidade de Lisboa
• Subject(s): Immunobiology; Immunotherapy; Lymphoid neoplasia
• Document Type: Journal article
• Language: English
• Contributor(s): Repositório Científico de Acesso Aberto da ULisboa

Description

The downstream signaling of the interleukin-7 (IL-7) receptor (IL-7R) plays important physiological and pathological roles, including the differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain-of-function mutations in the IL-7Rα chain, the specific component of the receptor for IL-7, result in constitutive, IL-7-independent signaling and trigger acute lymphoblastic leukemia. Here, we show that the loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) and causes an altered dynamic structure of the IL-7 receptor. We discovered that the IL-7Rα chain contains a very conserved positively charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region; this region establish stronger ionic interactions with negatively charged PtdIns(4,5)P2 in the absence of INPP5K, freezing the IL-7Rα chain structure. This dynamic structural alteration causes defects in IL-7R signaling, culminating in decreased expressions of EBF1 and PAX5 transcription factors, in microdomain formation, cytoskeletal reorganization, and bone marrow B-cell differentiation. Similar alterations after the reduced INPP5K expression also affected mutated, constitutively activated IL-7Rα chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyzes PtdIns(4,5)P2, allowing the requisite conformational changes of the IL-7Rα chain for optimal signaling.