LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses.

Increased activity of leucine-rich repeat kinase 2 (LRRK2) is an important risk factor for Parkinson's disease. LRRK2 localizes to lysosomal membranes, and changes in lysosome physiology are emerging as key regulators of its activation, yet the mechanisms by which distinct perturbations engage this kinase remain unclear. Analysis of osmotic and membrane-integrity challenges revealed that LRRK2 integrates multiple upstream cues through parallel interactions with Rab GTPases and GABARAP. Manipulations that caused lysosome enlargement, including inhibition of PIKfyve, showed that osmotic swelling leads to the accumulation of multiple Rabs on lysosomes and Rab-dependent LRRK2 activation independently of GABARAP. In contrast, under conditions of lysosome deacidification, CASM-dependent lipidation of GABARAP creates a platform that cooperates with Rabs in LRRK2 activation. These findings demonstrate how LRRK2 interprets perturbations of lysosome function through a combination of Rab- and GABARAP-dependent mechanisms, providing a framework for understanding both normal physiological regulation and pathological dysregulation in Parkinson's disease.