# Molecular mechanisms for lipid sensing by mTORC1

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $357,810

## Abstract

PROJECT SUMMARY
 The molecular mechanisms through which cells sense nutrients remain largely unknown, but their
elucidation is key to our understanding of metabolic regulation both in normal and disease states. At the center
of nutrient sensing and growth regulation is an ancient protein kinase known as the mechanistic Target of
Rapamycin Complex 1 (mTORC1). In response to the combined action of metabolic inputs such as nutrients,
growth factors, energy and oxygen, mTORC1 translocates from the cytoplasm to the surface of lysosomes,
where its kinase function becomes activated. Accumulating evidence indicates that aberrant mTORC1 activation
at the lysosome could be a driving force in diseases ranging from cancer to type-2 diabetes to
neurodegeneration. Thus, a deep mechanistic understanding of how mTORC1 is activated in response to
nutrients could point the way to novel therapeutic strategies in these diseases.
 The current proposal investigates a central aspect of mTORC1 function that has so far remained
understudied and poorly understood, namely, its ability to sense lipids. We will build on our recent discovery that
mTORC1 senses an important lipid, cholesterol, at the lysosome. Using innovative approaches both in cells and
in vitro, we will address and elucidate key aspects of newly identified signaling pathway. In particular, we will
determine i) the cellular location of the cholesterol pools that regulate mTORC1 ii) the transport circuits that make
cholesterol available to mTORC1 and iii) the molecular mechanisms through which cholesterol induces mTORC1
recruitment to the lysosomal surface. Moreover, we will investigate how cholesterol sensing by mTORC1
depends on the Niemann-Pick C1 protein, loss of which causes a fatal metabolic and neurodegenerative
disease.
 We will address these research aims via innovative and highly complementary approaches recently
optimized in our lab, including measurement and targeted manipulations of the lipid content of selected organelle
populations, combined with reconstitution-based assays of mTORC1 regulation.
 Our findings will impact the current understanding of the molecular mechanisms of cellular lipid
homeostasis, and will point the way to novel approaches to manipulate mTORC1 signaling in disease settings.

## Key facts

- **NIH application ID:** 10144480
- **Project number:** 5R01GM127763-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Roberto Zoncu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,810
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144480

## Citation

> US National Institutes of Health, RePORTER application 10144480, Molecular mechanisms for lipid sensing by mTORC1 (5R01GM127763-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144480. Licensed CC0.

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