Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1

Abstract

Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified LYsosomal CHOlesterol Signaling (LYCHOS, previously annotated as G-protein coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1). Cholesterol bound to the N-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a GTPase-activating protein for the Rag guanosine triphosphatases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing, and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.

ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

“…3D ). Indeed, prior work has determined that cholesterol directly activates mTORC1 (Castellano et al, 2017; Davis et al, 2021; Lim et al, 2019; Shin et al, 2022). Consistent with our proteomics data, we found that gene sets related to cholesterol synthesis were increased in both cell lines with p16 knock-down and patients with low CDKN2A expression ( Fig.…”

“…The de novo synthesis pathway is a multi-step process starting with acetyl-CoA and progressing through the mevalonate pathway including conversion of HMG-CoA to mevalonate by the rate limiting enzyme HMG-CoA reductase and then cholesterol synthesis via squalene and lanosterol leading to cholesterol (Shi et al, 2022). Prior work has shown that cholesterol directly activates mTORC1 via LYCHOS at lysosomes (Castellano et al, 2017; Davis et al, 2021; Lim et al, 2019; Shin et al, 2022). Cholesterol has also been linked to genome instability, yet it has been placed upstream of DNA damage accumulation (Liu et al, 2023).…”

The paracaspase MALT1 controls cholesterol homeostasis in glioblastoma stem-like cells through lysosome proteome shaping

“…Likewise, our data show that the addition of exogenous cholesterol rescues both cell viability and the degradative capacities of lysosomes in MALT-on cells. Whether MALT1 operates upstream of the lysosomal cholesterol-sensing machinery remains to be explored [29][30][31]36 . Moreover, the fact that tumor cells relying on MALT1 activity for their survival 53,68,69,79,80 exhibits selective sensitivity to NPC1 inhibition raises the possibility that the paracaspase might coordinate the overall organization of the lysosomal compartment toward cholesterol handling.…”

“…Accordingly, lysosomes have been attributed crucial roles in nutrient and lipid sensing, and therefore metabolism 28 . Several proteins acting as sensors, including NPC1, LYCHOS, and SLC38A9, were described to gauge cholesterol levels in lysosomes and further transmit the information to the cell [29][30][31] . In this context, the serine/threonine kinase mTOR plays a pivotal role.…”

Longin domain GAP complexes in nutrient signalling, membrane traffic and neurodegeneration

“…In the nutrient signalling area, it remains unclear what are the physiological stimuli for GATOR1 to transition from its inhibitory binding state to its GAP active binding mode. In an exciting advance, cholesterol binding to the lysosomal membrane protein LYCHOS was shown to modulate GATOR1 activity [68]. Further understanding will likely require consideration of the roles of the GATOR2 and KICSTOR complexes, whose functions are still murky.…”