PKG and NHR-49 signalling co-ordinately regulate short-term fasting-induced lysosomal lipid accumulation in C. elegans.
Lysosomes act as terminal degradation organelles to hydrolyse macromolecules derived from both the extracellular space and the cytoplasm. In Caenorhabditis elegans fasting induces the lysosomal compartment to expand. However, the molecular and cellular mechanisms for this stress response remain largely unclear. In the present study, we find that short-term fasting leads to increased accumulation of polar lipids in lysosomes. The fasting response is co-ordinately regulated by EGL-4, the C. elegans PKG (protein kinase G) orthologue, and nuclear hormone receptor NHR-49. Further results demonstrate that EGL-4 acts in sensory neurons to enhance lysosomal lipid accumulation through inhibiting the DAF-3/SMAD pathway, whereas NHR-49 acts in intestine to inhibit lipids accumulation via activation of IPLA-2 (intracellular membrane-associated calcium-independent phospholipase A2) in cytoplasm and other hydrolases in lysosomes. Remarkably, the lysosomal lipid accumulation is independent of autophagy and RAB-7-mediated endocytosis. Taken together, our results reveal a new mechanism for lysosomal lipid metabolism during the stress response, which may provide new clues for investigations of lysosome function in energy homoeostasis.
*Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Wen-ming
WM
Huang
*Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Zhao-yu
ZY
Li
*Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Yan-jun
YJ
Xu
*Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Wei
W
Wang
†National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Mao-ge
MG
Zhou
†National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Peng
P
Zhang
†National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Ping-sheng
PS
Liu
Tao
T
Xu
*Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Zheng-xing
ZX
Wu
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005215:Fasting / Q000009:adverse effects; D006867:Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054512:Phospholipases A2, Calcium-Independent / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D015854:Up-Regulation
D029742:Caenorhabditis elegans Proteins; C108738:DAF-3 protein, C elegans; C505159:NHR-49 protein, C elegans; D009419:Nerve Tissue Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D051785:Smad Proteins; D017869:Cyclic GMP-Dependent Protein Kinases; C470349:EGL-4 protein, C elegans; D006867:Hydrolases; D054512:Phospholipases A2, Calcium-Independent