Identification of TNFAIP2 as a unique cellular regulator of CSF-1 receptor activation
Randa A Abdelnaser1, Masateru Hiyoshi2, Naofumi Takahashi1
1Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
Abstract:
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.
Insights
The cellular protein TNFAIP2 regulates CSF-1 receptor (CSF1R) activation by promoting its aggregation through PIP2 binding. This mechanism enhances CSF1R dimerization and macrophage response, offering therapeutic insights.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- The colony-stimulating factor 1 receptor (CSF1R) is crucial for macrophage development and a therapeutic target in oncology.
- Mechanisms regulating CSF1R activation and aggregate formation in macrophages remain incompletely understood.
Purpose of the Study:
- To identify novel regulators of CSF1R activation and aggregate formation.
- To elucidate the molecular mechanism by which TNFAIP2 influences CSF1R function.
Main Methods:
- Investigated the role of TNF-α-induced protein 2 (TNFAIP2) in CSF1R regulation using knockdown and overexpression studies in macrophages and 293 cells.
- Assessed CSF1R aggregate formation, activation, and cellular distribution of phosphatidylinositol 4,5-bisphosphate (PIP2) using biochemical and cell imaging techniques.
- Mutagenesis of PIP2-binding motifs in CSF1R and TNFAIP2 was employed to determine their functional significance.
Main Results:
- TNFAIP2 was identified as a novel regulator that promotes CSF1R aggregate formation and enhances CSF-1-induced CSF1R activation.
- Inhibition or knockdown of TNFAIP2 reduced CSF1R aggregation and macrophage responsiveness to CSF-1.
- Both CSF1R and TNFAIP2 bind PIP2; TNFAIP2 alters PIP2 cellular distribution, and disruption of PIP2 binding or depletion reduces CSF1R aggregation.
Conclusions:
- TNFAIP2 facilitates CSF1R aggregate formation by interacting with PIP2, thereby promoting CSF1R monomer proximity and efficient dimerization/activation upon CSF-1 stimulation.
- These findings reveal a novel regulatory pathway for CSF1R activation involving TNFAIP2 and PIP2, with implications for macrophage biology and cancer therapy.
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