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LRRK 2 activation controls the repair of damaged endomembranes in macrophages
Author(s) -
Herbst Susanne,
Campbell Philip,
Harvey John,
Bernard Elliott M,
Papayannopoulos Venizelos,
Wood Nicholas W,
Morris Huw R,
Gutierrez Maximiliano G
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104494
Subject(s) - biology , microbiology and biotechnology , lrrk2 , rab , escrt , autophagy , endomembrane system , gtpase , intracellular , endosome , biochemistry , mutation , apoptosis , endoplasmic reticulum , gene , golgi apparatus
Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or lysophagy are poorly characterised. Here, we show that the Parkinson's disease ( PD )‐related kinase LRRK 2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK 2 recruits the Rab GTP ase Rab8A to damaged endolysosomes as well as the ESCRT ‐ III component CHMP 4B, thereby favouring ESCRT ‐mediated repair. Conversely, in the absence of LRRK 2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK 2 gain‐of‐function mutations result in the accumulation of endolysosomes which are positive for the membrane damage marker Galectin‐3. Altogether, this work indicates that LRRK 2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK 2, and providing a new link between membrane damage and PD .