鉴定TNFAIP2作为CSF-1受体活化的独特细胞调节剂。

IF 3.3 2区 生物学 Q1 BIOLOGY
Life Science Alliance Pub Date : 2025-02-12 Print Date: 2025-05-01 DOI:10.26508/lsa.202403032
Randa A Abdelnaser, Masateru Hiyoshi, Naofumi Takahashi, Youssef M Eltalkhawy, Hidenobu Mizuno, Shunsuke Kimura, Koji Hase, Hiroshi Ohno, Kazuaki Monde, Akira Ono, Shinya Suzu
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引用次数: 0

摘要

编码酪氨酸激酶的CSF-1受体(CSF1R)是组织巨噬细胞发育所必需的,也是许多肿瘤的治疗靶点。然而,CSF1R的激活是如何调控的还不完全清楚。在这里,我们发现细胞蛋白TNF-α-诱导蛋白2 (TNFAIP2)是CSF1R的独特调节因子。CSF1R通过未知机制在巨噬细胞中形成大聚集体。抑制或敲低TNFAIP2可减少巨噬细胞对CSF-1的CSF1R聚集形成和功能反应,这与CSF-1刺激后CSF1R活化降低一致。当在293细胞中表达时,TNFAIP2增强了CSF1R聚集的形成和csf -1诱导的CSF1R活化。CSF1R和TNFAIP2结合细胞磷脂酰肌醇4,5-二磷酸(PIP2)。去除CSF1R或TNFAIP2的PIP2结合基序,或耗尽细胞PIP2,可减少CSF1R聚集体的形成。此外,TNFAIP2改变了PIP2的细胞分布。由于CSF-1诱导的CSF1R的二聚化对其激活至关重要,我们的研究结果表明,TNFAIP2通过PIP2增强CSF1R聚集体的形成,PIP2使CSF1R单体相互靠近,使CSF1R响应CSF-1有效地二聚化和激活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of TNFAIP2 as a unique cellular regulator of CSF-1 receptor activation.

The receptor of CSF-1 (CSF1R) encoding tyrosine kinase is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how CSF1R activation is regulated. Here, we identify the cellular protein TNF-α-induced protein 2 (TNFAIP2) as a unique regulator of CSF1R. CSF1R forms large aggregates in macrophages via unknown mechanisms. The inhibition or knockdown of TNFAIP2 reduced CSF1R aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced CSF1R activation after CSF-1 stimulation. When expressed in 293 cells, TNFAIP2 augmented CSF1R aggregate formation and CSF-1-induced CSF1R activation. CSF1R and TNFAIP2 bind the cellular phosphatidylinositol 4,5-bisphosphate (PIP2). The removal of the PIP2-binding motif of CSF1R or TNFAIP2, or the depletion of cellular PIP2 reduced CSF1R aggregate formation. Moreover, TNFAIP2 altered the cellular distribution of PIP2. Because CSF-1-induced dimerization of CSF1R is critical for its activation, our findings suggest that TNFAIP2 augments CSF1R aggregate formation via PIP2, which brings CSF1R monomers close to each other and enables the efficient dimerization and activation of CSF1R in response to CSF-1.

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来源期刊
Life Science Alliance
Life Science Alliance Agricultural and Biological Sciences-Plant Science
CiteScore
5.80
自引率
2.30%
发文量
241
审稿时长
10 weeks
期刊介绍: Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.
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