BMP pathway regulation of insulin signaling components promotes lipid storage in Caenorhabditis elegans

James F. Clark, Emma J. Ciccarelli, Peter Kayastha, Gehan Ranepura, Katerina K. Yamamoto, Muhammad S. Hasan, Uday Madaan, Alicia Meléndez, Cathy Savage-Dunn

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not fully understood. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing additional IIS functions including dauer formation, aging, and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

Original languageEnglish
Article numbere1009836
JournalPLoS Genetics
Volume17
Issue number10
DOIs
StatePublished - 11 Oct 2021
Externally publishedYes

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