Integrin-dependent trafficking of CD98hc reduces endocytic noise to maintain metabolic homeostasis

A stable supply of amino acids is essential for cellular homeostasis. CD98hc is an indispensable component of the LAT1 amino acid transporter. Here, we found an unexpected role for β1-integrin in amino acid homeostasis via the regulation of CD98hc trafficking. We identified Fast Endophilin-Mediated Endocytosis (FEME) as the primary internalization route for CD98hc in both osteosarcoma and brain endothelial cells. Endocytosis was followed by β1-integrin-dependent recycling, which diverted CD98hc from early endosomes. By combining mathematical modelling with high-content imaging, we demonstrate that this trafficking pathway exhibited emergent properties that filtered high-frequency endocytic events to stabilize CD98hc at the plasma membrane. Mutating CD98hc to disrupt its interaction with β1-integrin led to redistribution of the transporter into early endosomes, reduced intracellular amino acid levels and impaired growth under metabolic stress. We propose that regulation of transporter trafficking dynamics is a general mechanism to buffer endocytic noise and maintain metabolic homeostasis.