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.

中文翻译：

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LRRK2 激活控制巨噬细胞中受损内膜的修复。

细胞通过修复损伤或靶向受损的内溶酶体以通过溶酶体降解来响应内溶酶体损伤。然而，调节修复或溶血决定的信号特征很差。在这里，我们表明帕金森病 (PD) 相关激酶 LRRK2 在巨噬细胞中被病原体或无菌诱导的内膜损伤激活。LRRK2 将 Rab GTPase Rab8A 募集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，在没有 LRRK2 和 Rab8A 的情况下，受损的内溶酶体靶向溶血。这些观察结果在 PD 患者的巨噬细胞中得到了概括，其中致病性 LRRK2 功能获得性突变导致内溶酶体的积累，这些内溶酶体对膜损伤标志物 Galectin-3 呈阳性。共，