HR3/RORα-mediated cholesterol sensing regulates TOR signaling

Abstract

Abstract 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 RORα, 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 while also restraining longer-term responses through genomic regulation. We also find that RORα is necessary for cholesterol-mediated TOR activation in human cells, suggesting that HR3/RORα-mediated signaling 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.