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

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-7Ra 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-7Ra chain contains a very conserved positively charged polybasic amino acid sequence in its cyto-plasmic juxtamembrane region; this region establish stronger ionic interactions with negatively charged PtdIns(4,5)P2 in the absence of INPP5K, freezing the IL-7Ra 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-7Ra 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-7Ra chain for optimal signaling.

Automated summary

The downstream signaling of IL-7R plays important roles in lymphoid cell differentiation and proliferation of acute lymphoblastic leukemia cells. The loss of INPP5K leads to altered IL-7 receptor structure, resulting in defective IL-7 signaling and impaired B-cell differentiation. Reduced expression of INPP5K also affects mutated IL-7Ra chains, leading to reduced cell proliferation in leukemia.