# Feeding Drives HSF1 Transcriptional Programs Required for Global Protein Synthesis

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2020 · $380,250

## Abstract

Project summary
We have found that feeding activates previously unrecognized transcriptional programs in liver and muscle
designed to maintain protein folding homeostasis, or proteostasis. Heat shock factor 1 (HSF1), the master
transcription factor that controls the heat shock response (HSR), regulates and is required for these normal
physiological responses. The programs are inhibited by fasting, and hyperstimulated by refeeding after fasting.
The setting and pattern of regulation, inhibition by fasting and activation in liver and muscle by feeding closely
resembles mTOR responses. We further found that the HSF1 transcriptional program is in fact downstream of
the canonical Tsc1/2-Rheb-mTORC1 axis and is required for mTOR-dependent protein synthesis. Regulation
appears to go both ways. Inhibition of mTOR suppresses the HSF1 transcriptional response, and HSF1 loss-
of-function in liver suppresses both mTOR activation and protein synthesis. mTOR regulation clearly
distinguishes the HSF1 feeding response from a classical heat shock response, which is not regulated by
mTOR. Transcriptome-wide RNA-seq results further distinguish the hepatic feeding response from the HSR, as
fewer than 10% of genes are common to both responses. The RNA-seq results also show that feeding induces
an unfolded protein response (UPR) in the ER, which is distinct from the cytoplasmic protein folding response
(cPFR) we describe. While cytoplasmic and ER protein folding responses are distinguished by both subcellular
distribution and proteins/pathways involved, they appear to be mechanistically linked, as perturbations in one
affect the other (e.g. the XBP1s transcriptional program is suppressed in Hsf1 null liver). Based on our
preliminary findings we hypothesize: 1) Feeding acutely increases protein synthesis and therefore the protein
folding burden in liver and muscle. 2) mTOR simultaneously promotes protein synthesis and the cellular
machinery for maintaining proteostasis. 3) HSF1 loss of function increases the cytoplasmic protein folding
burden, which 4) suppresses mTOR-dependent protein synthesis and thereby 5) reduces the protein folding
burden in both cytoplasm and ER. Similarly, 6) XBP1 loss of function induces ER stress, which suppresses
mTOR dependent protein synthesis and the protein folding burden in both cytoplasm and ER, which suggest 7)
cross-talk between cytoplasmic and ER protein folding responses. We contrast the physiological feeding
responses in muscle and liver with the classical HSR at all levels, regulation, transcriptional programs, and
effects of HSF1 on both mTOR and the ER protein folding response. Aims 1-3 test hypotheses related to
feeding, whereas Aim 4 asks whether the proposed mechanisms extend more broadly to other settings of
mTOR-dependent protein synthesis. Aim 4 thus hypothesizes that like feeding, 1) exercise coordinately drives
mTOR-dependent protein synthesis and an HSF1 transcriptional program required for proteostasis and muscle
grow...

## Key facts

- **NIH application ID:** 9891051
- **Project number:** 5R01DK112153-03
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** STEVEN E SHOELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,250
- **Award type:** 5
- **Project period:** 2018-05-02 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891051

## Citation

> US National Institutes of Health, RePORTER application 9891051, Feeding Drives HSF1 Transcriptional Programs Required for Global Protein Synthesis (5R01DK112153-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9891051. Licensed CC0.

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