# Investigating Biomolecular Condensates and Heat Shock Proteins in Cellular Responses to Sublethal Heat Shock and Fever

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2024 · $53,974

## Abstract

Project Summary
 Environmental temperature dictates biology. Animals use their thermal environments to guide their
migration, circadian rhythms, growth, feeding, and sex determination: essential behaviors now threatened by
changing climates. Warming temperatures likewise challenge human health. About 1 in 100 deaths globally stem
from heat-related causes, and such mortality is rising. Beyond lethal heatstroke, more mild heat affects human
health in far more common and pervasive ways. Heat <40°C alters and dysregulates human physiology down to
the cellular level, particularly in immune cells. Such sublethal heat shocks occur in hyperthermia and heat illness,
as well as frequently in fever: a systemic heat shock which regulates the immune system during infection. Yet
even in the well-known context of fever, we lack understanding of how human cells sense sublethal heat shock.
 The cell biology of extreme heat shock >40°C is well-characterized, but far less is understood about
sublethal, fever-range temperatures <40°C. However, we do know that certain immune cells upregulate heat
shock protein expression in response to fever. The induction of heat shock proteins, or the heat shock response,
occurs in eukaryotes when heat activates transcription factor Hsf1, via titration of its repressor (heat shock protein
Hsp70) away from Hsf1. This titration is caused by the generation of new, heat shock-induced substrates for
Hsp70 to bind. These substrates, i.e. the upstream sensors of heat, are unidentified in sublethal heat shock.
 We hypothesize biomolecular condensates are these substrates which help cells sense sublethal heat
shock. Condensation, or reorganization of proteins and RNA into larger foci, occurs in response to environmental
stimuli across species from yeast to humans. Our group showed recently that heat-induced condensates are
Hsp70 substrates in yeast. We hypothesize that sublethal heat shock-induced condensates are Hsp70
substrates in humans, enabling cells to sense and respond to such fever-range temperatures. It is not known
what proteins condense in human cells at these temperatures, nor if such condensates might be Hsp70
substrates. Moreover, in any species, we lack molecular-scale understanding of how condensates and Hsp70
interact. We are poised to unlock exactly this knowledge using a complement of biochemical, microscopic, and
molecular-level approaches. First, we will uncover protein condensation in human cell lines at fever-range
temperature, using the established sedimentation-mass spectrometry method of our group. Second, we will
observe directly how condensates and Hsp70 interact at the molecular scale, using single-molecule microscopy.
Together, these aims will help us elucidate fundamentally how cells sense and respond to sublethal heat shock.

## Key facts

- **NIH application ID:** 10843079
- **Project number:** 5F30ES035279-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Kyle Matthew Lin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843079

## Citation

> US National Institutes of Health, RePORTER application 10843079, Investigating Biomolecular Condensates and Heat Shock Proteins in Cellular Responses to Sublethal Heat Shock and Fever (5F30ES035279-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10843079. Licensed CC0.

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