HR3/RORα-mediated cholesterol sensing regulates TOR signaling

Cells and organisms adjust their growth based on the availability of cholesterol, which is essential for cellular functions. However, the mechanisms by which cells sense cholesterol levels and translate these into growth signals are not fully understood. We report that cholesterol rapidly activates the master growth-regulatory TOR pathway in Drosophila tissues. We identify the nuclear receptor HR3, an ortholog of mammalian ROR, as an essential factor in cholesterol-induced TOR activation. We demonstrate that HR3 binds cholesterol and promotes TOR pathway activation through a non-genomic mechanism acting upstream of the Rag GTPases. Similarly, we find that ROR is necessary for cholesterol-mediated TOR activation in human cells, suggesting that HR3/ROR represents a conserved mechanism for cholesterol sensing that couples cholesterol availability to TOR-pathway activity. These findings advance our understanding of how cholesterol influences cell growth, with implications for cholesterol-related diseases and cancer. HighlightsO_LICholesterol leads to dynamic TOR pathway activation, driving systemic growth C_LIO_LIHR3 in Drosophila binds cholesterol and couples its availability to TOR activation C_LIO_LIHR3 acts upstream of Rag GTPases to activate TOR in response to lysosomal cholesterol C_LIO_LIMammalian HR3 ortholog ROR is required for cholesterol-induced TOR activation C_LI