Insights into ‘garbage trucks’ of cells improves understanding of human diseases

Research led by Francis Crick Institute scientists has revealed insights into how a process called autophagy happens in cells, with implications for increasing understanding of cancer and other human diseases.

Dr Sharon Tooze of the Crick (currently based at Lincoln's Inn Fields) said: "To remain healthy, cells must dispose of their unwanted or damaged components. If these damaged components accumulate, they can stop the cell performing its normal function, resulting in diseases like Alzheimer's and Parkinson's disease, or lead to DNA damage which can lead to cancer-causing mutations. One of the main ways cells dispose of these potentially dangerous materials is through a 'self-eating' process called autophagy.

"Autophagy can be thought of as a recycling system.  Unwanted cellular components are engulfed by unique membrane compartments called autophagosomes.  Autophagosomes act as garbage trucks, carrying the unwanted material to the cell's recycling plant, the lysosome.  Here the autophagosome's contents are broken down into their constituent parts which can be re-used by the cell."

When a cell is stressed it can form dozens of autophagosomes in just 15 minutes - this requires major reorganisation of the membranes inside the cell. Dr Tooze's laboratory is working to understand how autophagosomes form. One of the questions they are addressing is how this reorganisation of membranes is controlled by the cell.

In previous work the researchers discovered a protein called TBC1D14 that helps to decode growth signals from the outside the cell, and also controls the formation of autophagosomes. To investigate how TBC1D14 works they used mass spectrometry, a technique which allows them to identify unknown proteins which associate with known proteins. This revealed that a multi-protein assembly, known as the TRAPP complex, interacts with TBC1D14. 

The TRAPP complex acts in the cell to maintain essential functions such as secretion, the process of releasing chemicals and other molecules from a cell that is important for tissue and organ function. Genetic mutations in the TRAPP complex cause a rare disease that affects skeletal tissue.

Dr Tooze's team showed that TBC1D14 and the TRAPP complex act together to control autophagy. This is important because it provides a link between outside events, such as growth signals (through TBC1D14), and those required to maintain the cell's environment (via the TRAPP complex) with the autophagy response to stress. The scientists suggest that these links allow the cell to respond to variations in its normal function by activating a survival pathway.

Dr Tooze said: "Autophagy increases when cells are stressed, such as in starvation conditions. This is what happens in many tumours and it is thought that cancer cells exploit autophagy to survive this starvation. Understanding how autophagy is controlled is important, as the process can either protect against or support disease progression in different contexts."

"Our work into the fundamental process of how proteins interact may also help in understanding other human diseases, such as rare diseases that arise by unexpected changes in a cell's proteins."

The paper, TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic, is published in the EMBO Journal.

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