Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans

Xuepiao Pu; Bin Qi

doi:10.1016/j.celrep.2024.114138

Lysosomal dysfunction by inactivation of V-ATPase drives innate immune response in C. elegans

Cell Rep. 2024 Apr 26;43(5):114138. doi: 10.1016/j.celrep.2024.114138. Online ahead of print.

Authors

Xuepiao Pu¹, Bin Qi²

Affiliations

¹ Southwest United Graduate School, Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
² Southwest United Graduate School, Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China. Electronic address: qb@ynu.edu.cn.

PMID: 38678555
DOI: 10.1016/j.celrep.2024.114138

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 (UPR^mt). The inactivation of V-ATPase promotes the nuclear localization of DVE-1, activating UPR^mt 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.

Keywords: C. elegans; CP: Immunology; UPR(mt); V-ATPase; immunity; lysosomes; mitochondria; mitochondrial surveillance; pathogen.