Endosomes manage key metabolic activities through their phosphoinositides, particularly PI(4,5)P2, which modulates membrane dynamics. Upon Pseudomonas aeruginosa infection, increased RAB-10 activity in C. elegans triggers a defense cascade involving UNC-16-mediated recruitment of EGL-8. This interaction reduces PI(4,5)P2 while increasing DAGs, activating the PMK-1/p38 MAPK pathway. When RAB-10 is absent, DAG production is impaired, weakening innate immune responses. Similarly, UNC-16 deficiency disrupts endosomal DAG homeostasis. The nuclear receptor NHR-25 was identified as essential for the infection-induced upregulation of LET-413, which activates RAB-10. These findings position endosomal PI(4,5)P2 catabolism as a critical immune modulator and provide evolutionary insights into innate immunity mechanisms.
Key findings from the study include:

1. Role of RAB-10 in Innate Immunity

RAB-10 activity increases in the intestine during P. aeruginosa infection, enhancing innate immune responses. RAB-10 mutants exhibited impaired responses due to reduced DAG production and PMK-1 pathway activation, affirming its essential regulatory role.

2. UNC-16 as a RAB-10 Effector

UNC-16 forms dimers that interact with RAB-10 to recruit EGL-8 to sorting endosomes. This recruitment facilitates PI(4,5)P2 hydrolysis, linking DAG generation to immune activation. UNC-16 deficiency mirrors RAB-10 mutants, showing reduced DAG levels and compromised immunity.

3. NHR-25 and LET-413 in RAB-10 Activation

NHR-25 facilitates LET-413 expression, enabling RAB-10 activity in response to pathogens. This transcriptional regulation ties environmental detection to molecular immune defenses.

4. Broader Implications for PI(4,5)P2 Catabolism

The study underscores the centrality of PI(4,5)P2 catabolism in orchestrating cellular responses, extending its relevance from vesicular trafficking to immune resilience..
This work identifies endosomal PI(4,5)P2 catabolism as a fundamental process in pathogen resistance. The synergistic actions of RAB-10, UNC-16, and NHR-25 orchestrate metabolic changes critical for activating the PMK-1 pathway, establishing a robust immune response. These findings enrich our understanding of endosomal dynamics in innate immunity and offer a model for further exploration in higher organisms. The work entitled “ Endosomal Catabolism of Phosphatidylinositol 4,5-Bisphosphate: Building Resilience Against Pathogens” was published on Protein & Cell (published on Aug. 1, 2024).
DOI: 10.1093/procel/pwae041