The lysosomal membrane protein SCAV-3 maintains lysosome integrity and adult longevity

• Published in: The Journal of cell biology Vol. 215; no. 2; pp. 167 - 185
• Main Authors: Li, Yuan, Chen, Baohui, Zou, Wei, Wang, Xin, Wu, Yanwei, Zhao, Dongfeng, Sun, Yanan, Liu, Yubing, Chen, Lianwan, Miao, Long, Yang, Chonglin, Wang, Xiaochen
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 24.10.2016; The Rockefeller University Press
• Subjects: Animals; Autophagy; Caenorhabditis elegans - cytology; Caenorhabditis elegans - physiology; Caenorhabditis elegans - ultrastructure; Caenorhabditis elegans Proteins - metabolism; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Endosomes - metabolism; Endosomes - ultrastructure; Glycosylation; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Green Fluorescent Proteins - metabolism; Hydrolases - metabolism; Insulin - metabolism; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Intracellular Membranes - metabolism; Intracellular Membranes - ultrastructure; Lipids; Longevity; Lysosomes - metabolism; Lysosomes - ultrastructure; Membrane Proteins - metabolism; Membranes; Metabolites; Molecules; Mutation - genetics; Nematodes; Protein Stability; Signal Transduction
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201602090

Lysosomes degrade macromolecules and recycle metabolites as well as being involved in diverse processes that regulate cellular homeostasis. The lysosome is limited by a single phospholipid bilayer that forms a barrier to separate the potent luminal hydrolases from other cellular constituents, thus protecting the latter from unwanted degradation. The mechanisms that maintain lysosomal membrane integrity remain unknown. Here, we identified SCAV-3, the Caenorhabditis elegans homologue of human LIMP-2, as a key regulator of lysosome integrity, motility, and dynamics. Loss of scav-3 caused rupture of lysosome membranes and significantly shortened lifespan. Both of these phenotypes were suppressed by reinforced expression of LMP-1 or LMP-2, the C. elegans LAMPs, indicating that longevity requires maintenance of lysosome integrity. Remarkably, reduction in insulin/insulin-like growth factor 1 (IGF-1) signaling suppressed lysosomal damage and extended the lifespan in scav-3(lf) animals in a DAF-16-dependent manner. Our data reveal that SCAV-3 is essential for preserving lysosomal membrane stability and that modulation of lysosome integrity by the insulin/IGF-1 signaling pathway affects longevity.