LRRK2 to the rescue of damaged endomembranes

Abstract

Mutations in several genes encoding for lysosomal proteins are involved in Parkinson's disease (PD). In this issue, Herbst et al (2020) show that PD-related leucine-rich repeat kinase 2 (LRRK2) is activated in response to pathogen or membranolytic drug-induced damage of phagolysosomes and lysosomes in macrophages, and regulates endolysosomal homeostasis by controlling the balance between membrane repair and degradation.

Figure 1. LRRK2 activation controls the repair of damaged endomembranes in macrophages

In macrophages, LRRK2 activation is triggered by pathogen or chemically induced damage of phagolysosome or lysosome. Once activated, LRRK2 phosphorylates the small GTPase Rab8A which, in response to Ca²⁺ flux out of the lysosome, recruits the ESCRT‐III protein CHMP4B to mediate endolysosomal membrane repair. In the absence of LRRK2 and Rab8A, the recruitment of ESCRT‐III is impaired and lysophagy is initiated by galectin‐3, which recruits LC3B‐containing autophagic membranes to initiate clearance of the damaged lysosome by lysophagy.