Research Overview
Decoding Stress Responses to Promote Health and Combat Disease
At the Thibault Lab, we take a multi-organism approach to uncover the evolutionarily conserved stress response pathways that underpin both cellular resilience and dysfunction. Our work spans basic mechanistic biology, clinically relevant disease models, and computational tool development, with the goal of advancing both fundamental understanding and therapeutic innovation.
Key Areas of Research
ER Stress, Lipid Bilayer Stress, and IRE1 Signaling
The endoplasmic reticulum is the cell's primary hub for protein folding and lipid homeostasis. When either is perturbed, the unfolded protein response (UPR) is activated. We showed that ER stress arises from two mechanistically distinct inputs: proteotoxic stress, caused by the accumulation of misfolded proteins, and lipid bilayer stress (LBS), caused by membrane perturbation. Each recruits the UPR but deploys a distinct transcriptional programme.
The master UPR sensor IRE1 is central to our work. IRE1 splices XBP1 mRNA to produce the transcription factor XBP1s and degrades other ER-localized transcripts through regulated IRE1-dependent decay (RIDD). We recently found that aging shifts IRE1 activity away from XBP1 splicing and toward enhanced RIDD, dysregulating critical cellular functions. We are now dissecting the molecular basis of this substrate-preference switch and its consequences for cell physiology during aging and metabolic disease.
ER-Phagy and Organelle Quality Control
Cells maintain ER health through ER-phagy, the selective autophagy pathway that clears damaged ER fragments via lysosomal degradation. We discovered that IRE1 is not merely a stress sensor. It plays an essential, constitutive role in driving the terminal ER-lysosome fusion step required to complete ER-phagy.
This pathway fails with age. Senescent cells lose XBP1s expression and accumulate stalled ER-phagosomes, phenocopying IRE1-knockout cells. Restoring XBP1s reverses this defect. We are now mapping the pathway, defining how it is regulated, and testing whether its restoration can reverse age-related proteostatic decline in polarized epithelial cells and human intestinal organoids.
Host-Pathogen Interactions in Chronic Wound Healing
Chronic skin wounds represent a major clinical challenge, and bacterial infection is a key driver of healing failure. We focus on Enterococcus faecalis, a common wound pathogen whose virulence mechanisms remain poorly understood. We showed that E. faecalis potently activates the UPR in host keratinocytes and fibroblasts, blocking the cell migration required for wound closure.
The trigger is extracellular hydrogen peroxide generated by the bacterium's extracellular electron transport (EET) system, not classical respiration, as previously assumed. This H₂O₂ induces lipid peroxidation in host membranes, which activates the UPR through lipid bilayer stress. We demonstrated this using a screen of nearly 15,000 bacterial mutants. Removing the EET system or neutralizing H₂O₂ with catalase fully rescues keratinocyte migration. We are now dissecting the host signalling pathways that link lipid peroxidation to UPR activation and ferroptosis.
Integrative Bioinformatics and Systems Tools
Biology is increasingly data-rich. Our lab develops computational pipelines that combine natural language processing, gene interaction mining, and multi-species transcriptomics to extract meaningful insights from complex datasets. We integrate data from scientific literature, public RNA-seq repositories, and our own experimental models to map how UPR gene networks are regulated across organisms and disease contexts. These tools support target discovery across all our research programmes.
Research Vision
Our goal is to understand how stress responses, particularly the UPR, can be selectively tuned to protect against cellular damage. This requires identifying key regulators, understanding their context-specific roles, and building tools to map their activity across systems. The same core pathway governs responses to misfolded proteins, membrane damage, bacterial infection, and the slow erosion of aging. We study all of these, because the connections between them are where the most important biology lives.
