Proteostasis

Although Lys48-linked ubiquitin is the canonical signal for protein clearance by the proteasome, ‘alternative’ ubiquitin signals play critical yet poorly-characterised roles in misfolded protein clearance—especially under acute stress. Using linkage-specific ubiquitin probes and perturbation tools, we are uncovering how these additional ubiquitin signalling events maintain proteome robustness in a range of physiologic and stressed cellular contexts.

Loss of proteostasis and cellular senescence are two well-established hallmarks of “normal” ageing, and are linked to almost all major ageing-associated chronic diseases. We are systematically investigating the inter-dependence of these two ageing hallmarks, with the goal of identifying proteostasis network vulnerabilities that could be exploited therapeutically to modulate the senescent cellular state.