# The Ragulator complex and lysosomal calcium release are crucial for cell migration

## TL;DR

Lysosomes help immune cells move by releasing calcium, and a drug called ouabain can stop this process, reducing inflammation.

## Contribution

The study reveals how lysosomal calcium release and the Ragulator complex regulate immune cell migration and identifies ouabain as a potential anti-inflammatory agent.

## Key findings

- Calcium efflux from TRPML1 channels enhances the interaction between the Ragulator complex and MPRIP, promoting leukocyte migration.
- Ouabain disrupts Lamtor1's lysosomal localization, inhibiting myosin IIA activation and cell migration.
- Ouabain reduces inflammation in gouty arthritis and lung injury models by suppressing leukocyte infiltration.

## Abstract

Lysosomal calcium efflux via TRPML1 drives leukocyte migration by enhancing Lamtor1–MPRIP interaction, and ouabain improves pathogenic inflammation by disrupting Lamtor1’s lysosomal localization.

Immune cells migrate via actomyosin contractility mediated by myosin IIA activation, wherein the lysosomal Ragulator complex–MPRIP interaction is crucial. However, the precise mechanism underlying lysosome-mediated myosin IIA activation has not been elucidated. Here, we found that calcium efflux from the lysosomal TRPML1 channel promotes leukocyte trafficking by enhancing the interaction between the Ragulator complex and MPRIP. Disrupting the lysosome-anchoring site of Lamtor1 impaired the localization of the Ragulator complex to lysosomes, diminishing the TRPML1-mediated leukocyte migration and interaction between Lamtor1 and MPRIP. Furthermore, ouabain, a cardiac glycoside, dissociated Lamtor1 from lysosomes, inhibiting the interaction between the Ragulator complex and myosin IIA activation, thereby suppressing cell migration. Therapeutically, ouabain ameliorated the severity of MSU-induced gouty arthritis and LPS-induced lung injury in mice by inhibiting leukocyte infiltration. Overall, lysosomes facilitate the interaction between the Ragulator complex and MPRIP by supplying calcium ions through TRPML1 channels, thereby activating myosin IIA and promoting leukocyte migration.