The lysosomal membrane protein SCAV-3 maintains lysosome integrity and adult longevity.
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.
College of Life Sciences, China Agriculture University, Beijing 100094, China.|National Institute of Biological Sciences, Beijing 102206, China.
Yuan
Y
Li
National Institute of Biological Sciences, Beijing 102206, China.
Baohui
B
Chen
National Institute of Biological Sciences, Beijing 102206, China.
Wei
W
Zou
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Xin
X
Wang
National Institute of Biological Sciences, Beijing 102206, China.
Yanwei
Y
Wu
National Institute of Biological Sciences, Beijing 102206, China.
Dongfeng
D
Zhao
National Institute of Biological Sciences, Beijing 102206, China.
Yanan
Y
Sun
National Institute of Biological Sciences, Beijing 102206, China.
Yubing
Y
Liu
Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Lianwan
http://orcid.org/0000-0002-5501-9118
L
Chen
Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Long
http://orcid.org/0000-0002-0562-6681
L
Miao
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Chonglin
http://orcid.org/0000-0002-4104-7855
C
Yang
National Institute of Biological Sciences, Beijing 102206, China wangxiaochen@nibs.ac.cn.
Xiaochen
http://orcid.org/0000-0002-4344-0925
X
Wang
D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006867:Hydrolases / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure; D008136:Longevity; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D055550:Protein Stability; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; D007328:Insulin; D008565:Membrane Proteins; C000619643:SCAV-3 protein, C elegans; D049452:Green Fluorescent Proteins; D007334:Insulin-Like Growth Factor I; D006867:Hydrolases