Rahul Samant
The accumulation of misfolded or otherwise non-native proteins in the cell is linked to an array of ageing-related disorders, including cancers and neuro-degenerative diseases. Healthy cells limit the toxicity of misfolded proteins by promoting their clearance and maintaining proteome balance: a process we call ‘proteostasis’.
The importance of discovering the two major pathways for misfolded protein clearance—the ubiquitin-proteasome system and autophagy—was highlighted by their recognition with Nobel Prizes in 2004 and 2016, respectively. How they are integrated to maintain proteostasis, however, is poorly understood. Addressing this question is the central scientific driver of our lab. Given that loss of proteostasis—including decline in both proteasomal and autophagic degradation—is a major hallmark of ageing, investigating the co-ordination between protein clearance pathways in young and aged cells will provide insights into improving health and well-being across the life-course.
We use a multi-disciplinary approach with an emphasis on mass spectrometry-based proteomic methods together with cutting-edge cell and molecular biology tools for probing ubiquitin-mediated protein clearance pathways. By performing studies in a range of model systems—from single-celled budding yeast, to humans—we hope to unravel underlying rules governing proteostasis conserved throughout evolution, development, and ageing.
Our current focus is on the use of drugs targeting the molecular chaperone HSP90—a key regulator of proteostasis—to investigate the plasticity of protein clearance pathways in young, aged, and diseased cells.
Drugs targeting the molecular chaperone HSP90 in cancer cells trigger clearance of cancer-causing proteins. Here, the oncoprotein HER2/ERBB2 (green)—normally at the cell surface (left) gets internalised for clearance following 8 hours of HSP90 inhibitor treatment (middle). By 24 hours, the protein is undetectable (right). Cell nuclei shown in blue.
From Samant, Clarke & Workman (2014).
Latest Publications
Alternative systems for misfolded protein clearance: life beyond the proteasome. The FEBS journal, 1, 1, 01 Nov 2020 PMID: 33135311 |
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Dosage compensation plans: protein aggregation provides additional insurance against aneuploidy. Genes & development, 33, 1549-5477, 2019 PMID: 31371460 |
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Methods for measuring misfolded protein clearance in the budding yeast Saccharomyces cerevisiae. Methods in enzymology, 619, 1557-7988, 2019 PMID: 30910025 |