LRRK 2 to the rescue of damaged endomembranes
| Autor: | Harald Stenmark, Maja Radulovic |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Endosomes
Biology Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mice 0302 clinical medicine Animals Humans Lysosomal proteins News & Views Molecular Biology Gene Pathogen 030304 developmental biology 0303 health sciences General Immunology and Microbiology Endosomal Sorting Complexes Required for Transport Kinase General Neuroscience Macrophages Parkinson Disease Intracellular Membranes LRRK2 3. Good health Cell biology Enzyme Activation RAW 264.7 Cells rab GTP-Binding Proteins Lysosomes 030217 neurology & neurosurgery Homeostasis |
| Zdroj: | The EMBO Journal EMBO J EMBO Journal |
| ISSN: | 0261-4189 |
| DOI: | 10.15252/embj.2020106162 |
| Popis: | 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 LRRK2 is activated in macrophages by pathogen- or sterile-induced endomembrane damage. LRRK2 recruits the Rab GTPase Rab8A to damaged endolysosomes as well as the ESCRT-III component CHMP4B, thereby favouring ESCRT-mediated repair. Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK2 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 LRRK2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage and PD. |
| Databáze: | OpenAIRE |
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