The kinase GSK-3 alters the RNA-binding protein landscape of lipid metabolism transcripts leading to altered expression in the C. elegans nervous system

Tissue-specific regulation of gene expression is essential for multicellular organisms, and RNA-binding proteins play central roles in these molecular processes. To determine how the Caenorhabditis elegans RNA-binding protein, ADR-1, regulates tissue-specific gene expression, we profiled the RNA-binding targets of ADR-1 in neural cells and assessed the effects of ADR-1 binding on neural gene expression. We identified a cohort of neural transcripts that function in lipid metabolism and are directly regulated by ADR-1 binding. To identify cellular factors that influence ADR-1 binding, a forward genetic screen was performed, revealing that the serine/threonine protein kinase, glycogen synthase kinase-3 (GSK-3), inhibits ADR-1 binding to the cohort. Further investigation revealed that the RNA-binding protein VIG-1 physically interacts with ADR-1, and the two proteins coordinately bind the neural lipid metabolism transcripts. Additional experiments revealed that VIG-1 is phosphorylated in a GSK-3-dependent manner, which inhibits the VIG-1–ADR-1 complex from binding the regulon in wild-type animals. Importantly, inhibition of GSK-3 kinase activity in wild-type animals also resulted in decreased neural expression of lipid metabolism genes. Together, we reveal that the interplay between a kinase and RNA-binding proteins regulates the expression of lipid metabolism genes within neural cells, potentially impacting stress resistance and longevity.