# Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B

## TL;DR

This paper shows how TBC1D9B and TMEM55B regulate lysosome function and positioning through ARL8B, impacting cell metabolism and stress responses.

## Contribution

The study identifies TBC1D9B as a novel GTPase-activating protein that negatively regulates ARL8B to control lysosome dynamics.

## Key findings

- TBC1D9B directly binds and activates ARL8B-GTP, regulating lysosome positioning.
- Loss of TBC1D9B or TMEM55B leads to lysosome dispersion and impaired autophagy.
- Defects caused by TBC1D9B loss are reversed by depleting ARL8, confirming its regulatory role.

## Abstract

Lysosomes are highly dynamic organelles that serve antagonistic functions as terminal catabolic stations for the degradation of macromolecules and as central metabolic decision centers for anabolic growth signaling. Lysosome dysfunction is implicated in various human diseases. The physiological roles of lysosomes are linked to the control of lysosome position and dynamics via the activity of the kinesin-activating small GTPase ARL8. How the activity of ARL8 is regulated remains poorly understood. Here, we identify the GTPase-activating Tre-2/Bub2/Cdc16 (TBC) domain protein TBC1D9B as a critical negative regulator of ARL8B function. We demonstrate that TBC1D9B is associated with the lysosomal membrane protein TMEM55B, directly binds to ARL8B-GTP, and stimulates its GTPase activity. Knockout of TBC1D9B or its binding partner TMEM55B causes lysosome dispersion, defective autophagic flux, and impairs the adaptive degradative response of cells to limiting nutrient supply. These lysosomal phenotypes of TBC1D9B loss are occluded by concomitant depletion of ARL8 in cells. Collectively, our data unravel a key role for TBC1D9B in controlling lysosome function by serving as a negative regulator of ARL8 activity.

Lysosome positioning is essential for cell metabolism and stress responses. Here, the authors show that the TMEM55B-associated protein TBC1D9B controls lysosome positioning, autophagy, and starvation-induced degradation by serving as a GTPase activating protein of ARL8B