A non-catalytic role of IPMK is required for PLCγ1 activation in T cell receptor signaling by stabilizing the PLCγ1-Sam68 complex.

Autor: Hong S; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Kim K; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Shim YR; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Park J; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Choi SE; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Min H; School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, 08826, Republic of Korea., Lee S; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Song JJ; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Kang SJ; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Jeong WI; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea., Seong RH; School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, 08826, Republic of Korea., Kim S; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Youseong-Gu, Daejeon, 34141, Republic of Korea. seyunkim@kaist.ac.kr.; KAIST Institute for the BioCentury, KAIST, Daejeon, 34141, Republic of Korea. seyunkim@kaist.ac.kr.; KAIST Stem Cell Center, KAIST, Daejeon, 34141, Republic of Korea. seyunkim@kaist.ac.kr.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Oct 30; Vol. 22 (1), pp. 526. Date of Electronic Publication: 2024 Oct 30.
DOI: 10.1186/s12964-024-01907-0
Abstrakt: Background: Phospholipase C gamma 1 (PLCγ1) is an important mediator of the T cell receptor (TCR) and growth factor signaling. PLCγ1 is activated by Src family kinases (SFKs) and produces inositol 1,4,5-triphosphate (InsP 3 ) from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme with broad substrate specificity and non-catalytic activities that mediate various functional protein-protein interactions. Therefore, IPMK plays critical functions in key biological events such as cell growth. However, the contribution of IPMK to the activation of PLCγ1 in TCR signaling remains mostly unelucidated. The current study aimed to elucidate the functions of IPMK in TCR signaling and to uncover the mode of IPMK-mediated signaling action in PLCγ1 activation.
Methods: Concanavalin A (ConA)-induced acute hepatitis model was established in CD4 + T cell-specific IPMK knockout mice (IPMK ΔCD4 ). Histological analysis was performed to assess hepatic injury. Primary cultures of naïve CD4 + T cells were used to uncover the role of mechanisms of IPMK in vitro. Western blot analysis, quantitative real-time PCR, and flow cytometry were performed to analyze the TCR-stimulation-induced PLCγ1 activation and the downstream signaling pathway in naïve CD4 + T cells. Yeast two-hybrid screening and co-immunoprecipitation were conducted to identify the IPMK-binding proteins and protein complexes.
Results: IPMK ΔCD4 mice showed alleviated ConA-induced acute hepatitis. CD4 + helper T cells in these mice showed reduced PLCγ1 Y783 phosphorylation, which subsequently dampens calcium signaling and IL-2 production. IPMK was found to contribute to PLCγ1 activation via the direct binding of IPMK to Src-associated substrate during mitosis of 68 kDa (Sam68). Mechanistically, IPMK stabilizes the interaction between Sam68 and to PLCγ1, thereby promoting PLCγ1 phosphorylation. Interfering this IPMK-Sam68 binding interaction with IPMK dominant-negative peptides impaired PLCγ1 phosphorylation.
Conclusions: Our results demonstrate that IPMK non-catalytically promotes PLCγ1 phosphorylation by stabilizing the PLCγ1-Sam68 complex. Targeting IPMK in CD4 + T cells may be a promising strategy for managing immune diseases caused by excessive stimulation of TCR.
(© 2024. The Author(s).)
Databáze: MEDLINE
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