TCF25 emerges as a cytoplasmic regulator of GPRASP2 stability

Protein homeostasis is central to cellular function, yet the factors regulating it are incompletely defined. TCF25 is a conserved eukaryotic protein whose cellular localisation and functional context remain poorly understood. Here, we investigate the distribution and interaction landscape of TCF25 under basal conditions using complementary imaging, biochemical fractionations and proximity-labelling approaches. We find that TCF25 is predominantly cytoplasmic across multiple human cell types, with a digitonin-resistant perinuclear pool indicative of association to membrane-linked compartments. Proximity proteomics defines the spatially-adjacent interactome of TCF25, including the G-protein coupled receptor-associated sorting protein GPRASP2, and reveals enrichment of intracellular membrane-associated components. We further show that TCF25 regulates GPRASP2 protein stability, and that a L415P TCF25 variant disrupts this relationship. Together, these findings establish a cytoplasmic, membrane-proximal context for TCF25 and identify its functional interaction with GPRASP2. These findings support a role for TCF25 in proteostatic regulation and open avenues for understanding its contribution to cellular homeostasis and disease.