# Nexilin promotes calcium-dependent endo-lysosomal fission required for retrograde transport

## TL;DR

This paper shows that nexilin helps late endosomes and lysosomes divide properly by linking them to the cell's actin structure and calcium signals.

## Contribution

The study identifies nexilin as a novel actin regulator involved in calcium-dependent fission of late endosomes and lysosomes.

## Key findings

- Nexilin depletion causes enlargement of late endosomes and lysosomes due to inhibited fission.
- Nexilin interacts with Rab7b and TRPML1, and TRPML1 activation rescues the enlargement caused by nexilin depletion.
- Nexilin mediates calcium-dependent fission of late endosomes and lysosomes via the acto-myosin cytoskeleton.

## Abstract

Late endosomes and lysosomes (LE/Lys) are dynamic organelles primarily involved in the degradation of macromolecules within cells. Beyond this role, they are crucial for nutrient sensing, calcium signalling, cell proliferation and migration. The cytoskeleton is essential for the proper trafficking and function of LE/Lys. However, while the role of microtubules is well-established, the function of the actin cytoskeleton at LE/Lys is less understood. In this work, we performed an siRNA screen to identify actin regulators that play a role at LE/Lys. The screen revealed that the F-actin-binding protein nexilin regulates LE/Lys size as its depletion leads to their enlargement. We show that this is a consequence of inhibited LE/Lys fission and affects the retrograde transport from late endosomes to Golgi. Moreover, our data demonstrate that nexilin interacts with the small GTPase Rab7b and the lysosomal calcium channel TRPML1, and that TRPML1 activation rescues the LE/Lys enlargement caused by nexilin depletion. Taken together, our results indicate that nexilin mediates the interaction between LE/Lys and the acto-myosin cytoskeleton required for the calcium-dependent fission of these organelles.

The online version contains supplementary material available at 10.1186/s12964-025-02628-8.