Endosomal trafficking participates in lipid droplet catabolism to maintain lipid homeostasis

Wang Peng, Shu Chen, Jingyu Ma, Wenjie Wei, Naixin Lin, Jinchao Xing, Wenjing Guo, Heying Li, Liang Zhang, Kuiming Chan, Andrew Yen, Guangyu Zhu () and Jianbo Yue ()
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Wang Peng: City University of Hong Kong Shenzhen Research Institute
Shu Chen: City University of Hong Kong Shenzhen Research Institute
Jingyu Ma: Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Jiangsu Provincial University Key (Construction) Laboratory for Smart Diagnosis and Treatment of Lung Cancer, Duke Kunshan University
Wenjie Wei: Core Research Facilities, Southern University of Science and Technology
Naixin Lin: City University of Hong Kong Shenzhen Research Institute
Jinchao Xing: City University of Hong Kong Shenzhen Research Institute
Wenjing Guo: Analysis and Testing Center, Guangzhou Institute of Biomedicine and Health (GIBH) Chinese Academy of Sciences
Heying Li: Analysis and Testing Center, Guangzhou Institute of Biomedicine and Health (GIBH) Chinese Academy of Sciences
Liang Zhang: City University of Hong Kong Shenzhen Research Institute
Kuiming Chan: City University of Hong Kong Shenzhen Research Institute
Andrew Yen: Department of Biomedical Sciences, Cornell University
Guangyu Zhu: City University of Hong Kong Shenzhen Research Institute
Jianbo Yue: City University of Hong Kong Shenzhen Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The interplay between lipid droplets (LDs) and endosomes remains unknown. Here, we screen and synthesize AP1-coumarin, an LD-specific probe, by conjugating a fluorescent dye coumarin to a triazine compound AP1. AP1-coumarin labels all stages of LDs in live cells and markedly induces the accumulation of enlarged RAB5-RAB7 double-positive intermediate endosomes. The AP1-coumarin-labeled LDs contact these intermediate endosomes, with some LDs even being engulfed in them. When LD biogenesis is inhibited, the ability of AP1-coumarin to label LDs is markedly reduced, and the accumulation of enlarged intermediate endosomes is abolished. Moreover, blocking the biogenesis of LDs decreases the number of late endosomes while increasing the number of early endosomes and inhibits the endosomal trafficking of low-density lipoprotein (LDL) and transferrin. Correspondingly, interference with RAB5 or RAB7, either through knockdown or using dominant-negative mutants, inhibits LD catabolism, whereas the expression of a RAB7 constitutively active mutant accelerates LD catabolism. Additionally, CCZ1 knockdown not only induces the accumulation of intermediate endosomes but also inhibits LD catabolism. These results collectively suggest that LDs and endosomes interact and influence each other’s functions, and endosomal trafficking participates in the catabolic process of LDs to maintain lipid homeostasis.

Date: 2025
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DOI: 10.1038/s41467-025-57038-8

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