Collecting the right waste: insights into the molecular mechanism of p62-mediated autophagy

29/01/2018

Waste management is a big problem, and not only for us but also for our cells. In order to remain healthy, our cells must constantly collect and degrade the waste that is produced inside them. If this harmful material accumulates cells will ultimately die, affecting the health of the entire organism. For example, many degenerative diseases such as Alzheimer’s and Parkinson’s diseases are thought to arise from the accumulation of harmful waste inside the cells.

To prevent this, our cells have developed multiple mechanisms which enable them to identify and dispose of the waste material. One of these mechanisms is autophagy, during which cells package their waste into small organelles called autophagosomes, analogous to the disposal of the household rubbish inside waste bags. Similar to waste bags, that get delivered to dedicated incinerators for destruction and recycling, autophagosomes deliver their content into lysosomes, which are cellular organelles for the waste degradation and recycling.

In order to be efficiently packaged into autophagosomes, the waste first needs be correctly identified and collected.
“Imagine there’s something that went bad in your fridge”, explains group leader Sascha Martens, “you can’t let it stand there, but you can’t just throw the whole content of the fridge either. Cells have the same problem, they need to sort the waste from the good material to remain healthy”.

It was long known that in human cells a protein called p62 is needed for the collection of the waste. The importance of p62 is underpinned by mutations in its gene that result in various diseases including dementia. However, how p62 recognizes the waste and if it can do the job on its own was unclear. A team of researchers from the Martens lab, in collaboration with the Sachse lab at EMBL Heidelberg, has now gained fascinating insight into the mechanism of action of p62 by reconstituting the process in a test tube. In particular, in a recent publication in the EMBO Journal, they could show that small filaments of p62 come together to trap damaged proteins marked with chains of a small tag called ubiquitin. This capturing process is highly selective and only certain types of tagged proteins are collected into particles that become targets for autophagy.

“It’s like a fishing net for damaged proteins formed by crisscrossed p62 filaments” explains first author Gabriele Zaffagnini, “it’s amazing to watch these particles form spontaneously in front of your eyes under the microscope”.
“We believe that p62 surveys the cell’s interior: when damaged proteins start to accumulate over a critical level, p62 kicks in and collects them for removal through autophagy. Our results might have medical implications in the future,” concludes Sascha Martens.

Publication in EMBO Journal
Zaffagnini G, Savova A, Danieli A, Romanov J, Tremel S, Ebner M, Peterbauer T, Sztacho M, Trapannone R, Tarafder AK, Sachse C, Martens S: p62 filaments capture and present ubiquitinated cargos for autophagy.