Abstract：
Pathogens target vacuolar ATPase (V-ATPase) to inhibit lysosomal acidification or lysosomal fusion, causing lysosomal dysfunction. However, it remains unknown whether cells can detect dysfunctional lysosomes and initiate an immune response. In this study, we discover that dysfunction of lysosomes caused by inactivation of V-ATPase enhances innate immunity against bacterial infections. We find that lysosomal V-ATPase interacts with DVE-1, whose nuclear localization serves as a proxy for the induction of mitochondrial unfolded protein response (UPRmt). The inactivation of V-ATPase promotes the nuclear localization of DVE-1, activating UPRmt and inducing downstream immune response genes. Furthermore, pathogen resistance conferred by inactivation of V-ATPase requires dve-1 and its downstream immune effectors. Interestingly, animals grow slower after vha RNAi, suggesting that the vha-RNAi-induced immune response costs the most energy through activation of DVE-1, which trades off with growth. This study reveals how dysfunctional lysosomes can trigger an immune response, emphasizing the importance of conserving energy during immune defense.
摘要：
病原体靶向液泡ATP酶（V-ATP酶）以抑制溶酶体酸化或溶酶体融合，导致溶酶体功能障碍.然而,目前尚不清楚细胞是否能检测到功能失调的溶酶体并启动免疫反应。在这项研究中,我们发现，由V-ATPase失活引起的溶酶体功能障碍增强了对细菌感染的先天免疫。我们发现溶酶体V-ATPase与DVE-1相互作用，DVE-1的核定位是诱导线粒体未折叠蛋白反应（UPRmt）的代表。V-ATPase的失活促进DVE-1的核定位,激活UPRmt并诱导下游免疫应答基因。此外，V-ATPase失活赋予的病原体抗性需要dve-1及其下游免疫效应子。有趣的是,动物在vhaRNAi后生长较慢，这表明vha-RNAi诱导的免疫反应通过激活DVE-1消耗最多的能量，这与生长权衡。这项研究揭示了功能失调的溶酶体如何触发免疫反应，强调在免疫防御过程中保存能量的重要性。
