[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
Palmer, MJ, Mahajan, VS, Trajman, LC, et al. Interleukin-7 receptor signaling network: an integrated systems perspective. Cell Mol Immunol 5:2 (2008), 79–89.
Babon, JJ, Lucet, IS, Murphy, JM, Nicola, NA, Varghese, LN, The molecular regulation of Janus kinase (JAK) activation. Biochem J 462:1 (2014), 1–13.
McElroy, CA, Holland, PJ, Zhao, P, et al. Structural reorganization of the interleukin-7 signaling complex. Proc Natl Acad Sci U S A 109:7 (2012), 2503–2508.
Walsh, STR, Structural insights into the common γ-chain family of cytokines and receptors from the interleukin-7 pathway. Immunol Rev 250:1 (2012), 303–316.
Barata, JT, Durum, SK, Seddon, B, Flip the coin: IL-7 and IL-7R in health and disease. Nat Immunol 20:12 (2019), 1584–1593.
Almeida, ARM, Neto, JL, Cachucho, A, et al. Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. Nat Commun 12:1 (2021), 7268–7283.
Shochat, C, Tal, N, Bandapalli, OR, et al. Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med 208:5 (2011), 901–908.
Schurmans, S, Vande Catsyne, CA, Desmet, C, Moës, B, The phosphoinositide 5-phosphatase INPP5K: from gene structure to in vivo functions. Adv Biol Regul, 79, 2021, 100760.
Pernot, E, Terryn, S, Cheong, SC, et al. The inositol Inpp5k 5-phosphatase affects osmoregulation through the vasopressin-aquaporin 2 pathway in the collecting system. Pflugers Arch 462:6 (2011), 871–883.
Abdelrasoul, H, Werner, M, Setz, CS, et al. PI3K induces B-cell development and regulates B cell identity. Sci Rep 8:1 (2018), 1327–1341.
Clark, MR, et al. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol 14:2 (2014), 69–80.
Hirokawa, S, Sato, H, Kato, I, Kudo, K, EBF-regulating Pax5 transcription is enhanced by STAT5 in the early stage of B cells. Eur J Immunol 33:7 (2003), 1824–1829.
Ochiai, K, Maienschein-Cline, M, Mandal, M, et al. A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation. Nat Immunol 13:3 (2012), 300–307.
Reth, M, Nielsen, P, Signaling circuits in early B-cell development. Adv Immunol 122 (2014), 129–175.
Decker, T, Pasca di Magliano, M, McManus, S, et al. Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity 30:4 (2009), 508–520.
Roessler, S, Györy, I, Imhof, S, et al. Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Mol Cell Biol 27:2 (2007), 579–594.
Corcoran, AE, Smart, FM, Cowling, RJ, Crompton, T, Owen, MJ, Venkitaraman, AR, The interleukin-7 receptor α chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. EMBO J 15:8 (1996), 1924–1932.
Jiang, Q, Li, WQ, Hofmeister, RR, et al. Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members. Mol Cell Biol 24:14 (2004), 6501–6513.
Lin, JX, Migone, TS, Tsang, M, et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2:4 (1995), 331–339.
Venkitaraman, AR, Cowling, RJ, Interleukin-7 induces the association of phosphatidylinositol 3-kinase with the alpha chain of the interleukin-7 receptor. Eur J Immunol 24:9 (1994), 2168–2174.
Wofford, JA, Wieman, HL, Jacobs, SR, Zhao, Y, Rathmell, JC, IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111:4 (2008), 2101–2111.
Guala, D, Bernhem, K, Ait Blal, H, et al. Experimental validation of predicted cancer genes using FRET. Methods Appl Fluoresc, 6(3), 2018, 035007.
Li, L, Shi, X, Guo, X, Li, H, Xu, C, Ionic protein-lipid interaction at the plasma membrane: what can the charge do?. Trends Biochem Sci 39:3 (2014), 130–140.
Porcu, M, Kleppe, M, Gianfelici, V, et al. Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia. Blood 119:19 (2012), 4476–4479.
Aivazian, D, Stern, LJ, Phosphorylation of T cell receptor zeta is regulated by a lipid dependent folding transition. Nat Struct Biol 7:11 (2000), 1023–1026.
Arkhipov, A, Shan, Y, Das, R, et al. Architecture and membrane interactions of the EGF receptor. Cell 152:3 (2013), 557–569.
Chen, X, Pan, W, Sui, Y, et al. Acidic phospholipids govern the enhanced activation of IgG-B cell receptor. Nat Commun, 6, 2015, 8552.
Chouaki-Benmansour, N, Ruminski, K, Sartre, A-M, et al. Phosphoinositides regulate the TCR/CD3 complex membrane dynamics and activation. Sci Rep, 8(1), 2018, 4966.
Deford-Watts, LM, Tassin, TC, Becker, AM, et al. The cytoplasmic tail of the T cell receptor CD3 epsilon subunit contains a phospholipid-binding motif that regulates T cell functions. J Immunol 183:2 (2009), 1055–1064.
Endres, NF, Das, R, Smith, A, et al. Conformational coupling across the plasma membrane in activation of the EGF receptor. Cell 152:3 (2013), 543–556.
Heo, WD, Inoue, T, Park, WS, et al. PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane. Science 314:5804 (2006), 1458–1461.
Xu, C, Gagnon, E, Call, ME, et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ϵ cytoplasmic tyrosine-based motif. Cell 135:4 (2008), 702–713.
Zhang, H, Cordoba, S-P, Dushek, O, van der Merwe, PA, Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling. Proc Natl Acad Sci U S A 108:48 (2011), 19323–19328.