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We recently identified TNF-\u03b1-induced protein 2 (TNFAIP2) as a unique cellular regulator of CSF1R activation: TNFAIP2 increased the response of macrophages to CSF-1, which might be explained at least in part by the induction of CSF1R clustering by TNFAIP2, since CSF1R clusters accelerate CSF-1-induced CSF1R dimerization\/activation. Here, we report an enhanced trafficking of CSF1R to the cell surface as an additional mechanism by which TNFAIP2 increases macrophage response to CSF-1. The mutation in the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding site of TNFAIP2 or CSF1R, or the deprivation of cellular PIP2 reduced the enhanced CSF1R trafficking by TNFAIP2, indicating the importance of PIP2-mediated membrane localization of TNFAIP2 and CSF1R. Mechanistically, a small GTPase RalA and the exocyst complex involved in vesicle trafficking were required for the enhanced CSF1R trafficking by TNFAIP2. Interestingly, the RalA\u2014exocyst complex cascade was also required for the enhanced CSF1R clustering by TNFAIP2. Our results suggest that TNFAIP2 enhances intracellular trafficking and cluster formation of CSF1R through PIP2, RalA, and the exocyst complex, thereby increasing the macrophage response to CSF-1. Our results also suggest that TNFAIP2 regulates other receptor tyrosine kinases.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf151","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T12:38:41Z","timestamp":1761568721000},"source":"Crossref","is-referenced-by-count":0,"title":["TNFAIP2 increases macrophage response to CSF-1 through multiple effects on CSF-1 receptor"],"prefix":"10.1093","volume":"117","author":[{"given":"Randa A","family":"Abdelnaser","sequence":"first","affiliation":[{"name":"Division of Infection & Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University , Kumamoto 860-0811 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masateru","family":"Hiyoshi","sequence":"additional","affiliation":[{"name":"Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, Japan Institute for Health Security , Tokyo 208-0011 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