Structural biology of autophagy

Cells continuously synthesize proteins, reconstruct their organelles and cellular components, renew them and take up substances from outside. A cellular mechanism that counteracts and controls this on-going growth of organic matter is autophagy. This particular mechanism degrades everything that is no longer needed – and this includes pathogens as well. In this regard autophagy plays a central role in our immune response and the defence against infectious diseases. Here you can find out how our scientists are researching autophagy in order to fight against pathogens and infectious diseases.

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Autophagy is a cellular process, which involves, initially, the formation of a double membrane vesicle structure that wraps around cellular components, the “cargo”, targeted for degradation. By vesicle fusion, the “cargo” is subsequently delivered to lysosomes – small compartments surrounded by membranes that contain digestive enzymes. This mixture of enzymes breaks down the internalized “cargo”, and the degradation products are recycled in cellular synthesis processes.

Autophagy was first discovered in yeast. In this context it serves as mechanism, which allows cells to adapt to nutrient deprivation and starvation. But autophagy in mammalian cells is much more than just a cellular response to hunger. It is involved in many processes and of essential significance in infection and immunity. Defects in autophagy give rise to the onset of many diseases such as cancer, neurodegenerative diseases like Huntington and Parkinson, as well as chronic inflammation in the gastro-intestinal tract.

Autophagosome formation: core machinery and adaptations
(Zhiping Xie & Daniel J. Klionsky, Nature Cell Biology 9, 1102 - 1109, 2007)

Xeno-autophagy, a variation of autophagy, is a highly efficient defence mechanism against pathogenic germs that destroys these germs – in the ideal case. However, many pathogens not only know how to circumvent this defence mechanism; rather, they know how to use it for their own purposes as well. They make use of the vesicle formed during autophagy, in order to create a safe environment within the cell in which they can freely replicate sealed-off from the remainder of the cell.

Even though there is currently intensive on-going research on these processes, many details remain unexplained regarding the fundamental mechanisms of regulation of autophagy as well as the strategies for exploitation of autophagy by pathogens. Our scientists are getting to the bottom of these issues with X-ray crystallography, biochemical/biophysical and cell-biological methods. New findings will help to combat and manipulate pathogen-mediated infection processes, in order to ultimately re-activate the cellular defence mechanisms.

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