We study how cells sense and respond to changes in their environment. Our particular interest has been in cellular stress responses where cells must rapidly and decisively respond to sudden maladaptive changes. In all cellular life, certain stresses such as heat shock and oxidative stress lead to similar phenomena: large clusters of proteins and RNA form, a powerful transcriptional response is induced, and translational activity is reduced and redirected toward newly produced transcripts. Many of these transcripts encode molecular chaperones, long thought to mainly help cells clean up misfolded proteins resulting from stress. A dominant interpretation has been that of proteotoxic stress: stress causes protein and RNA misfolding, cells respond inducing genes that encode chaperones, and chaperones help clean up misfolding.

Our work has uncovered a remarkable alternative: adaptive condensation. Cells sense stress using biomolecular condensation—essentially domesticated phase transitions of proteins and RNA; chaperones are key regulators of condensation; and the entire process allows cells to rapidly respond to stress, rather than being burdened with damage that must be cleaned up. We have made key discoveries regarding the roles of molecular chaperones as regulators of biomolecular condensation, and how cells sense temperature and other stresses.

Biomolecular condensation—the assembly of cellular components into concentrated, spatially organized bodies—has emerged as a unifying mechanism across all of these areas.

Adaptive condensation in the stress response
image coming soon

We have shown that condensation of proteins and mRNAs during stress is adaptive, tuned by evolution, regulated by conserved molecular machinery, and key to understanding how cells nimbly sense and immediately respond to stressful conditions. Our most recent discovery of translation-initiation-inhibited condensates (TIICs, pronounced “ticks”) reveals how cells change their mind: condensing pre-stress mRNAs and excluding new mRNAs encoding stress-specific adaptive programs.

Key papers:
Molecular chaperones as condensation regulators
image coming soon

Molecular chaperones are best known for helping proteins fold. We study the ways in which chaperones also play a major role in regulating biomolecular condensation. Chaperones can disperse condensates, reshape their composition, and control their formation. We discovered that biochemically, chaperones are far more proficient at dispersing condensates than at disaggregating misfolded proteins. Understanding how chaperones work, how they are regulated, and how they engage their endogenous substrates including stress-triggered condensates, are major focus areas for the group.

Key papers:
How cells sense and interpret temperature
image coming soon

Temperature affects virtually every biological process, yet how cells actually sense temperature remains poorly understood. We have found that biomolecular condensation can act as a molecular thermometer: phase-separation temperatures of key proteins are tuned to organism-specific thermal thresholds. While temperature and heat shock have long been considered stresses that cells must respond to or die, the natural world is filled with examples of cells and organisms interpreting temperature as a key signal, not a stress. From how immune cells sense fever, to how pathogens use temperature-sensing to identify when they have encountered a warm-blooded host, to how yeast cells appear tuned to sense the body temperatures of birds that disperse them, we seek to understand how cells perceive temperature and convert this primordial signal into adaptive action.

Key papers: