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LRRK2-dependent Rab GTPase phosphorylation in response to endolysosomal damage depends on macrophage differentiation

Susanne Herbst, View ORCID ProfileMaximiliano G. Gutierrez
doi: https://doi.org/10.1101/2020.10.02.323873
Susanne Herbst
1Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK
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  • For correspondence: Susanne.Herbst@crick.ac.uk Max.G@crick.ac.uk
Maximiliano G. Gutierrez
1Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK
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  • ORCID record for Maximiliano G. Gutierrez
  • For correspondence: Susanne.Herbst@crick.ac.uk Max.G@crick.ac.uk
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Abstract

The Parkinson’s Disease (PD) kinase LRRK2 is highly expressed in immune cells such as macrophages. In these cells, LRRK2 regulates innate immune pathways and it is activated after membrane damage leading to the phosphorylation of the Rab GTPases Rab8A and Rab10. Due to their wide-range of functions in immunity and tissue remodelling, macrophages in vivo are phenotypically heterogeneous. In vitro systems are used to differentiate these cells into diverse macrophage subsets to mimic the populations observed in vivo. M-CSF and GM-CSF differentiated human blood monocytes are often used to generate monocyte-derived macrophages as a model for tissue macrophages. However, how LRRK2 is activated in different macrophage subsets after membrane damage is unknown.

Here, we report that bone marrow derived macrophages and human monocyte-derived macrophages differentiated with either M-CSF or GM-CSF show different levels of LRRK2 activation after membrane damage. Notably, the membrane damaging agent LLOMe triggered LRRK2-dependent Rab8A and Rab10 phosphorylation primarily in GM-CSF differentiated macrophages. Moreover, LRRK2 and Rab8A were recruited to damaged endolysosomes in GM-CSF differentiated macrophages. Strikingly, GM-CSF differentiated macrophages recruited significantly more CHMP4B and Galectin-3 into damaged endolysosomes. These results suggest that LRRK2-regulated pathways of endolysosomal membrane damage and repair differ between macrophage subsets.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 02, 2020.
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LRRK2-dependent Rab GTPase phosphorylation in response to endolysosomal damage depends on macrophage differentiation
Susanne Herbst, Maximiliano G. Gutierrez
bioRxiv 2020.10.02.323873; doi: https://doi.org/10.1101/2020.10.02.323873
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LRRK2-dependent Rab GTPase phosphorylation in response to endolysosomal damage depends on macrophage differentiation
Susanne Herbst, Maximiliano G. Gutierrez
bioRxiv 2020.10.02.323873; doi: https://doi.org/10.1101/2020.10.02.323873

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