LAT1 supports mitotic progression through Golgi unlinking in an amino acid transport activity-independent manner

Amino acid transporters are crucial for maintaining cellular homeostasis by supporting protein synthesis. Among them, L-type amino acid transporter 1 (LAT1/SLC7A5/CD98lc) is a key transporter of large neutral amino acids, especially in cancer cells, due to its predominant expression. Although restricting amino acids using analog treatments is known to cause mitotic defects, the role of amino acid transporters in cell division remains poorly understood.

In this study, we found that LAT1 is essential for mitotic progression through a mechanism independent of its transport activity. Knocking down LAT1 activates the spindle assembly checkpoint, resulting in a delay at metaphase. LAT1 ensures proper spindle orientation by confining the NuMA protein to the lateral cortex, where it regulates the pulling forces that align the mitotic spindle. Interestingly, inhibiting LAT1’s amino acid transport with JPH203 does not affect mitotic progression. Additionally, a LAT1 mutant lacking transport activity still maintains proper spindle orientation and mitotic progression.

LAT1 forms a heterodimer with CD98 (SLC3A2/CD98hc) during both interphase and mitosis. While CD98 knockdown reduces LAT1′s localization at the plasma membrane, it does not interfere with mitotic progression. Beyond the plasma membrane, LAT1 is also localized to the Golgi and ER during interphase, where it promotes Golgi unlinking as cells enter mitosis, facilitating centrosome maturation.

These findings suggest that LAT1 supports mitotic progression through mechanisms unrelated to amino acid transport, with Golgi-localized LAT1 playing a key role in promoting mitotic entry by accelerating Golgi unlinking and centrosome maturation. This study uncovers a novel function of LAT1 in cell division.