Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, UCL Movement Disorders Centre, University College London, London, UK.
EMBO J. 2020 Sep 15;39(18):e104494. doi: 10.15252/embj.2020104494. Epub 2020 Jul 9.
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.
细胞通过修复损伤或通过溶酶体吞噬作用靶向受损的内溶酶体来应对内溶酶体损伤。然而，调节修复或溶酶体吞噬作用的信号通路尚未得到很好的描述。在这里，我们表明，帕金森病（PD）相关激酶 LRRK2 可被病原体或非病原体诱导的内膜损伤激活。LRRK2 将 Rab GTPase Rab8A 招募到受损的内溶酶体，以及 ESCRT-III 成分 CHMP4B，从而有利于 ESCRT 介导的修复。相反，在缺乏 LRRK2 和 Rab8A 的情况下，受损的内溶酶体被靶向溶酶体吞噬作用。在 PD 患者的巨噬细胞中也观察到了这些现象，致病性 LRRK2 获得性功能突变导致内溶酶体积累，内溶酶体对膜损伤标志物半乳糖凝集素-3 呈阳性。总的来说，这项工作表明，LRRK2 通过控制膜修复和细胞器替换之间的平衡来调节内溶酶体稳态，揭示了 LRRK2 的一个意想不到的功能，并为膜损伤与 PD 之间提供了新的联系。
