Brian M. Castellano
Cell biologist who, in Roberto Zoncu's lab at UC Berkeley, showed that cholesterol inside the lysosome switches on mTORC1 through the SLC38A9 and NPC1 proteins
Department of Molecular and Cell Biology, University of California, Berkeley (Zoncu lab, papers 2015–2017, at the time of the study)
Castellano was first author of a 2017 Science paper in this Atlas (CAS2017). Every cell has to decide whether it has enough raw materials to grow. mTORC1, the growth-control complex, makes that decision on the surface of the lysosome, the cell's recycling compartment, where it is switched on when nutrients are present. Amino acids were the best-known signal; CAS2017 showed that cholesterol inside the lysosome is another one. SLC38A9, a transporter-like protein already known to sense the amino acid arginine, is needed for cholesterol to switch mTORC1 on, and it uses separate cholesterol-responsive parts of the protein to do it. NPC1, the protein that moves cholesterol out of the lysosome and is faulty in Niemann-Pick type C disease, binds SLC38A9 and holds mTORC1 back. The experiments used cell lines and fibroblasts from patients, not whole animals.
The finding opened a new line of work. If cholesterol feeds mTORC1, then diseases in which cholesterol gets stuck in lysosomes, like Niemann-Pick type C, may also disturb growth signalling, and later papers from the same lab followed this up.
During the Berkeley years Castellano also co-authored a 2015 Nature Genetics paper on recurrent mutations in RRAGC, a gene for one of the Rag GTPases that bring mTORC1 to the lysosome, which keep mTORC1 switched on in follicular lymphoma, and a 2017 Cell Reports study on how proteins from the bacterium Legionella pneumophila turn mTORC1 up and down. No current position could be confirmed, so the affiliation shown is the one on the Atlas paper.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 2017 | M | Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex CAS2017 First author: showed that lysosomal cholesterol activates mTORC1 through SLC38A9, and that NPC1 restrains this signal. |
Co-authors in the Atlas 6
People with a profile here who share at least one study with Brian M. Castellano.
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- Ashley M. Thelen Cell biologist who did graduate work in Roberto Zoncu's lysosome lab at UC Berkeley, first author of a 2017 review on the lysosome's roles in lipid metabolism, and later a postdoctoral scholar in Philip Greenberg's lab at Fred Hutch
- Daniel K. Nomura Chemical biologist and professor at UC Berkeley who uses chemoproteomics to find druggable sites on proteins, including covalent handles that turn ordinary drug molecules into protein degraders
- Douglas F. Covey Medicinal chemist and Andrew C and Barbara B Taylor Distinguished Professor of Psychiatry at Washington University in St. Louis who designs synthetic steroids and sterols to study neurosteroids, GABA-A receptors and cholesterol sensing, including in two Atlas studies on cholesterol and mTORC1
- Ofer Moldavski Researcher who worked on lysosomes and lipid signalling in Roberto Zoncu's lab at UC Berkeley and was first author of a 2021 study on how the oxysterol 4beta-hydroxycholesterol switches on fat-making genes
- Oliver B. Davis Cell biologist who did a PhD in Roberto Zoncu's lab at UC Berkeley on how lysosomal cholesterol controls mTORC1, and first author of a 2020 study proposing NPC1-mTORC1 signalling as a drug target in Niemann-Pick type C disease
- Rushika M. Perera Professor of Anatomy at UCSF whose lab studies how autophagy and the lysosome, the cell's recycling centre, help cancer cells cope with stress, and a co-author of two Science papers on how lysosomal cholesterol switches on mTORC1
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