Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinson’s disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here, we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase–ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase–ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

中文翻译：

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V-ATPase-ATG16L1 轴招募 LRRK2 以促进溶酶体应激反应


富含亮氨酸的重复激酶 2 (LRRK2) 是一种与帕金森病和多种炎症性疾病相关的 Rab 激酶，已被证明定位于应激溶酶体并被激活以调节溶酶体稳态。然而，LRRK2 招募和激活的机制尚未得到充分了解。在这里，我们发现 ATG8 缀合系统调节 LRRK2 和 LC3 募集到应激溶酶体/吞噬体的单膜上。这种招募不需要包含 FIP200 的自噬起始复合物，也不会发生在双膜自噬体上，表明独立于典型的自噬。一致地，LRRK2 的招募受到 V-ATPase-ATG16L1 轴的调节，该轴需要 ATG16L1 的 WD40 结构域，并特异性介导单膜上的 ATG8 脂化。该机制还负责溶酶体应激诱导的 LRRK2 激活以及由此产生的溶酶体分泌和增大的调节。这些结果表明，V-ATPase-ATG16L1 轴通过招募 LRRK2 在维持溶酶体稳态中发挥新的非自噬作用。