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bioRxiv · 10.1101/2025.08.15.670582

The neuropeptide neuromedin U receptor nmur-1 buffers insulin receptor signaling in bacteria-dependent C. elegans survival

Sifoglu, D.·Pereira, B.·DeGregory, C.·Shah, R.·Maier, W.·Guan, J.·Clark, I.·Patel, D.·Ch'ng, Q.·Alcedo, J.
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Abstract

Distinct microbial environments exert diverse effects on the physiology and survival of the nematode Caenorhabditis elegans. Here, we show that C. elegans grown on two Escherichia coli strains exhibit different survival dynamics. Wild-type C. elegans on the B type OP50 exhibit more early deaths compared to C. elegans on K-12 type CS180. These early deaths on OP50 are characterized by swollen pharynges (P-deaths) due to bacterial accumulation within the tissue. In contrast, animals on CS180 are more resistant to P-deaths. These bacteria-dependent differences in P-deaths depend on bacterial lipopolysaccharide structures and the activities of the C. elegans neuropeptide neuromedin U receptor NMUR-1, which reduces P-deaths on OP50, but not on CS180. Surprisingly, however, NMUR-1 promotes the opposite response when the insulin receptor DAF-2 has reduced function -- where NMUR-1 now stimulates P-deaths on OP50, but again with no effect on CS180. We also find that NMUR-1 acts in sensory neurons to promote its bi-directional effects on longevity, which depend on the FOXO transcription factor DAF-16. In addition, NMUR-1 downregulates the expression of the insulin-like peptide daf-28, but only when DAF-2 function is not reduced. This suggests a regulatory mechanism through which NMUR-1 maintains insulin receptor DAF-2 signaling at a suitable level. Thus, our studies reveal that NMUR-1 serves to buffer the dynamic range of DAF-2 receptor signaling, thereby optimizing pharyngeal health and survival in response to specific bacteria.

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Sifoglu, D., Pereira, B., DeGregory, C., Shah, R., Maier, W., Guan, J., Clark, I., Patel, D., Ch'ng, Q., Alcedo, J.. 2025-08-21. The neuropeptide neuromedin U receptor nmur-1 buffers insulin receptor signaling in bacteria-dependent C. elegans survival. https://doi.org/10.1101/2025.08.15.670582

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