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Article Abstract
Background & Aims: We previously identified a fasting- and CREB-H-induced (FACI) protein and defined its adaptor function in clathrin-mediated endocytosis. Both CREB-H and FACI are specifically expressed in the liver and intestine. Here, we investigated the role of FACI in macropinocytosis and its activation by protein kinase Cα.
Methods: We employed a combination of biochemical, proteomic, cell biological, and microbiological assays to investigate the function of FACI in cultured cells and FACI mice.
Results: Phosphorylation of FACI at S9 and S37 by protein kinase Cα induces its detachment from clathrin-coated pits and relocation to the plasma membrane. FACI promotes phorbol ester-induced macropinocytosis in intestinal and hepatic cells. Interactome analysis reveals that FACI interacts with several actin remodeling proteins. FACI interacts with 14-3-3ζ to release SSH1 phosphatase from sequestration. Free SSH1 activates cofilin-1, which in turn enhances actin remodeling and macropinocytosis. Intestinal pathogens such as Salmonella typhimurium exploit FACI to facilitate their entry into host cells through macropinocytosis.
Conclusion: FACI modulates clathrin-mediated endocytosis and macropinocytosis in intestinal and hepatic cells. Protein kinase Cα phosphorylates FACI to switch its function in endocytosis to a presumed role in macropinocytosis in these cells. FACI facilitates enteric pathogen invasion by enhancing macropinocytosis in the intestine.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302249 | PMC |
| http://dx.doi.org/10.1016/j.jcmgh.2025.101551 | DOI Listing |
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