Endosomal catabolism of phosphatidylinositol 4,5-bisphosphate is fundamental in building resilience against pathogens.

Chao YANG; Longfeng YAO; Dan CHEN; Changling CHEN; Wenbo LI; Hua TONG; Zihang CHENG; Yanling YAN; Long LIN; Jing ZHANG; Anbing SHI

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Endosomal catabolism of phosphatidylinositol 4,5-bisphosphate is fundamental in building resilience against pathogens.

Author: Chao YANG ¹ ; Longfeng YAO ¹ ; Dan CHEN ¹ ; Changling CHEN ¹ ; Wenbo LI ¹ ; Hua TONG ¹ ; Zihang CHENG ¹ ; Yanling YAN ¹ ; Long LIN ¹ ; Jing ZHANG ¹ ; Anbing SHI ¹
Author Information

1. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, China.
Publication Type:Journal Article
Keywords: C. elegans; EGL-8/PLC-β; NHR-25/NR5A1/2; PI(4,5)P2; RAB-10/Rab10; UNC-16/JIP3; sorting endosome
MeSH: Animals; Caenorhabditis elegans/genetics*; Endosomes/immunology*; Caenorhabditis elegans Proteins/immunology*; Phosphatidylinositol 4,5-Diphosphate/immunology*; Immunity, Innate; Pseudomonas aeruginosa/immunology*; rab GTP-Binding Proteins/genetics*; Diglycerides/metabolism*
From: Protein & Cell 2025;16(3):161-187
CountryChina
Language:English
Abstract: Endosomes are characterized by the presence of various phosphoinositides that are essential for defining the membrane properties. However, the interplay between endosomal phosphoinositides metabolism and innate immunity is yet to be fully understood. Here, our findings highlight the evolutionary continuity of RAB-10/Rab10's involvement in regulating innate immunity. Upon infection of Caenorhabditis elegans with Pseudomonas aeruginosa, an increase in RAB-10 activity was observed in the intestine. Conversely, when RAB-10 was absent, the intestinal diacylglycerols (DAGs) decreased, and the animal's response to the pathogen was impaired. Further research revealed that UNC-16/JIP3 acts as an RAB-10 effector, facilitating the recruitment of phospholipase EGL-8 to endosomes. This leads to a decrease in endosomal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and an elevation of DAGs, as well as the activation of the PMK-1/p38 MAPK innate immune pathway. It is noteworthy that the dimerization of UNC-16 is a prerequisite for its interaction with RAB-10(GTP) and the recruitment of EGL-8. Moreover, we ascertained that the rise in RAB-10 activity, due to infection, was attributed to the augmented expression of LET-413/Erbin, and the nuclear receptor NHR-25/NR5A1/2 was determined to be indispensable for this increase. Hence, this study illuminates the significance of endosomal PI(4,5)P2 catabolism in boosting innate immunity and outlines an NHR-25-mediated mechanism for pathogen detection in intestinal epithelia.