NEW STUDY. The protein VCP plays an important role in initiating the process of autophagy in the cell. This is the finding of researchers at the University of Gothenburg together with researchers at the University of Cambridge and AstraZeneca. Their study was recently published in the the journal Nature Chemical Biology.
Autophagy is the process that the cell uses to remove harmful proteins and to recycle building blocks and energy. It is a continually ongoing cleaning process that also can be used in the event of starvation when the cells need to redistribute energy and building blocks.
“Autophagy is a very important process and is regulated in so many ways, where each new discovery opens up the possibility of being able to pharmaceutically influence the process. If we could increase the capacity of cells to breakdown components through autophagy, we could potentially protect cells from impaired function from aging or prevent neurodegeneration,” says Sandra Malmgren Hill, a researcher at the Department of Psychiatry and Neurochemistry and the first author of the article.
The study was conducted when she was a postdoc at the University of Cambridge in a team led by Professor David Rubinsztein. He is also the corresponding author to the article in Nature.
Membrane bubble packs the recycling
In autophagy, a membrane bubble is formed that encloses the material to be broken down, which is then travels to the cell’s own recycling center where the material is broken down into new cellular components. This study shows that the levels of the lipid needed for the membrane bubble are regulated by the protein VCP. This protein is well studied and has been shown to have a function in many of the cell’s processes.
“It is difficult to genetically manipulate VCP. Since it is an essential protein, attempts often lead to systematic collapse and cell death. We were able to circumvent this problem by acutely blocking the function of VCP using commercially available chemical inhibitors. These inhibitors are small synthetic molecules that bind VCP and obstruct its function,” says Malmgren Hill.
In the study, the researchers describe how VCP regulates the onset of autophagy in two ways, both of which are dependent on another protein called Beclin-1. The study shows that if the function of VCP is blocked either genetically or with chemical inhibitors, the ability of cells to initiate the process of autophagy diminishes, making them less able to cope with starvation conditions. This is a previously unknown role for VCP.
Following up the study
The study is part of an ongoing collaboration with the University of Cambridge and researchers at AstraZeneca, which seeks to identify new mechanisms that control autophagy in hopes of finding a point that enables chemical modification using drugs.
“AstraZeneca’s expertise in neurochemistry and the opportunity to study protein activity and interactions on a large scale have been a huge help with this. We will continue our collaboration with AstraZeneca in a follow-up study where we aim to identify new molecules that can be used to regulate the function of VCP, and thereby influence the described role of VCP in the initiation of autophagy.”
Title: VCP/p97 regulates Beclin-1-dependent autophagy initiation; Sandra M Hill et al. Nat Chem Biol. DOI: 10.1038 / s41589-020-00726-x
BY: ELIN LINDSTRÖM