Project Reference: TRG27-BIO-KL1

Project title: Are all stress granules the same? Interrogation of cytosolic biocondensates formed in response to different types of celular stressors

Project outline

Upon cellular stress, proteins and RNA undergo phase separation into stress granules—membraneless cytosolic organelles. This coincides with global translational shutdown and is thought to protect mRNAs from degradation, triage transcripts for later translation or decay, conserve energy in line with the ISR, and act as a signalling hub influencing cell survival versus death. Granules are highly dynamic, and aberrant recruitment of protein and RNA species is linked to cancer, neurological disease, and therapy resistance, making their underlying mechanisms important therapeutic targets.

The Integrated Stress Response (ISR) is a conserved survival pathway activated by stressors such as nutrient deprivation, viral infection, and protein misfolding. It conserves energy through global translational attenuation while upregulating repair genes or, under irreparable stress, apoptosis. Four kinases—PERK, GCN2, HRI, and PKR—respond to distinct stress signals (ER misfolding, amino acid scarcity, low iron/heme, and viral infection, respectively) but converge on a single event: eIF2α phosphorylation, which drives stress granule formation. Whether this convergence yields a uniform cellular response, or whether kinase-specific factors shape the balance between recovery and apoptosis via differential protein/RNA recruitment, remains unclear.

This proposal aims to systematically compare stress granule formation across activation of each ISR kinase, using isogenic cell models with inducible, kinase-specific stress induction. The project will build on novel technologies developed in our labs, extending them to investigate how postranslational (e.g. phosphorylation and posttranscriptional modifications (e.g RNA methylation) influences granule recruitment. The project will involve RNA sequencing, mass spectrometry based proteomics, and application of AI tools to build integrated cellular models

Principal Supervisor

Professor Kathryn Lilley

Email address: k.s.lilley@bioc.cam.ac.uk

Department / Partner Institute: Biochemistry

Website: https://www.bioc.cam.ac.uk/research/lilley

BBSRC strategic theme

Transformative technologies