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PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.

ABSTRACT: Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by mediating oligomerization. Using an inducible knockout mouse model, we show that TrIP-deficient T cells exhibit more robust activation and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation.

SUBMITTER: Uche UU

PROVIDER: S-EPMC6279406 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.

Uche Uzodinma U UU Piccirillo Ann R AR Kataoka Shunsuke S Grebinoski Stephanie J SJ D'Cruz Louise M LM Kane Lawrence P LP

The Journal of experimental medicine 20181114 12

Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kri ...[more]

PMID: 30429249

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Project description:The present study aimed to investigate the effects of microRNA (miR)?21 on osteoclastogenesis and its underlying molecular mechanisms. The expression levels of tartrate?resistant acid phosphatase (TRAP) and miR?21 were detected during osteoclastogenesis in receptor activator of NF??B ligand (RANKL)?induced RAW264.7 cells via reverse transcription?quantitative PCR. Bioinformatics and dual luciferase reporter assays were performed to analyze the association between miR?21 and Pten. RANKL?induced RAW264.7 cells were divided into the following groups: MiR?negative control (NC), miR?21 mimic, miR?21 inhibitor and miR?21 mimic + LY294002. The effects of miR?21 on osteoclastogenesis and bone resorption were then detected using TRAP staining and a bone resorption assay. Pten, phosphorylated?Akt and nuclear factor of activated T cell (NFATc1) expression levels were measured by western blotting to analyze the effects of miR?21 on the PI3K/Akt signaling pathway. The present study revealed that miR?21 was upregulated during osteoclastogenesis in RANKL?induced RAW264.7 cells. Furthermore, miR?21 negatively regulated Pten. Compared with the miR?negative control (NC) group, the number of osteoclasts and the percentage of bone resorption were increased in the miR?21 mimic group, whereas they were decreased in the miR?21 inhibitor group. The number of osteoclasts and the percentage of bone resorption in the miR?21 mimic + LY294002 group were lower than in the miR?21 mimic group. Compared with the miR?NC group, the protein expression levels of Pten were decreased, whereas p?Akt and NFATc1 were increased in the miR?21 mimic group. Conversely, Pten protein expression was increased, whereas p?Akt and NFATc1 were decreased in the miR?21 inhibitor group. In the miR?21 mimic + LY294002 group, Pten protein expression was higher, and p?Akt and NFATc1 were lower than in the miR?21 mimic group. In conclusion, miR?21 is upregulated during osteoclastogenesis, and may promote osteoclastogenesis and bone resorption through activating the PI3K/Akt signaling pathway via targeting Pten.

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PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.

Publications

PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.

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