Identification of TNFAIP2 As a Unique Cellular Regulator of CSF-1 Receptor Activation

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2025 Feb 12

PMID 39939179

Authors

Randa A Abdelnaser

Masateru Hiyoshi

Naofumi Takahashi

Youssef M Eltalkhawy

Hidenobu Mizuno

Shunsuke Kimura

Koji Hase

Hiroshi Ohno

Kazuaki Monde

Akira Ono

Shinya Suzu

Affiliations

Soon will be listed here.

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.

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