Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland.
Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland.
Cell Mol Life Sci. 2024 Aug 19;81(1):356. doi: 10.1007/s00018-024-05396-9.
FGF12 belongs to a subfamily of FGF proteins called FGF homologous factors (FHFs), which until recently were thought to be non-signaling intracellular proteins. Our recent studies have shown that although they lack a conventional signal peptide for secretion, they can reach the extracellular space, especially under stress conditions. Here, we unraveled that the long "a" isoform of FGF12 is secreted in a pathway involving the A1 subunit of Na(+)/K(+) ATPase (ATP1A1), Tec kinase and lipids such as phosphatidylinositol and phosphatidylserine. Further, we showed that the short "b" isoform of FGF12, which binds ATP1A1 and phosphatidylserine less efficiently, is not secreted from cells. We also indicated regions in the FGF12a protein sequence that are crucial for its secretion, including N-terminal fragment and specific residues, and proposed that liquid-liquid phase separation may be important in this process. Our results strongly suggest that the mechanism of this process is very similar for all unconventionally secreted FGF proteins.
成纤维细胞生长因子 12（FGF12）属于成纤维细胞生长因子蛋白的一个亚家族，称为成纤维细胞同源因子（FHFs），这些因子直到最近才被认为是无信号的细胞内蛋白。我们最近的研究表明，尽管它们缺乏用于分泌的传统信号肽，但它们可以到达细胞外空间，特别是在应激条件下。在这里，我们揭示了 FGF12 的长“a”异构体是通过涉及 Na(+)/K(+)ATP 酶（ATP1A1）的 A1 亚基、 Tec 激酶和磷脂（如磷脂酰肌醇和磷脂酰丝氨酸）的途径进行分泌的。此外，我们表明，结合 ATP1A1 和磷脂酰丝氨酸效率较低的 FGF12 的短“b”异构体不会从细胞中分泌出来。我们还指出了 FGF12a 蛋白序列中对其分泌至关重要的区域，包括 N 端片段和特定残基，并提出液-液相分离可能在此过程中很重要。我们的研究结果强烈表明，所有非传统分泌的 FGF 蛋白的这个过程的机制非常相似。
