Autophagy transcriptional crosstalk: the LMX1A/LMX1B paradigm

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Autophagy is an important quality control process carried out by all cells to assist with their normal biological functions and to protect them from the stresses they inevitably encounter as part of multicellular life. It involves the packaging of damaged and potentially harmful cellular material into membrane-bound sacs (called autophagosomes) for delivery to the waste disposal centre of the cell. For this reason, autophagy is a key facet of normal tissue homeostasis across the lifespan, and is a critical protector against important human diseases including neurodegeneration, heart disease, diabetes and cancer. Over recent years we have learned much about how the autophagy process is regulated within cells - culminating in the award of a Nobel Prize in 2016 to Prof. Yoshinori Ohsumi, one of the pioneers in the field - but we still know relatively little about how the genes that oversee the autophagy process are controlled in response to stress. The process of gene expression (switching genes on) involves the binding of proteins called transcription factors to activating sites on the cell's DNA. We have found that an important pair of transcription factors - called LMX1A and LMX1B - switch on critical autophagy genes to help with the formation and function of cells in important organs such as the kidney and (parts of) the brain. Having confirmed roles for these transcription factors during autophagy gene expression, the challenge has been to better understand how they are themselves regulated. Surprisingly, we have discovered that a key protein needed for the formation of autophagosomes - called LC3 - binds to LMX1A/LMX1B to increase their ability to stimulate autophagy gene expression, meaning that the autophagy machinery can potentially control itself by switching on its own genes. In this proposal we aim to provide a clear picture of the molecular mechanisms central to this exciting finding, and by doing so we will determine whether this novel scenario extends to other autophagy and related transcription factors as part of concerted efforts to better understand how cells cope with stresses and challenges across the lifespan.This is a frontier bioscience project that seeks to understand fundamental processes in cell biology. That said, autophagy is essential for normal health in humans, animals and plants, being required during various stages of development and helping to keep tissues functioning normally during ageing. For this reason, autophagy is being vigorously researched as a potent pharmaceutical target in various diseases associated with ageing, notably neurodegeneration and cancer, and as a route to improve crop productivity and in bioengineering. Our efforts to better understand the potential crosstalk within the autophagy gene expression pathways in humans has the potential to be exploited in disease therapy, and for our part we will therefore examine how the novel pathway we have discovered impacts on the health of important cell types in brain (neurons) and kidney (podocytes) cell models.