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Developing our understanding of the fundamentals of autophagy

Key points:

• Researchers from the Signalling programme have identified an important new molecular feature of autophagy, a key cellular pathway in health and disease.
• The study focused on distinguishing the modifications that facilitate the dual role of the signalling molecule ATG8 in two distinct autophagy pathways.
• These results will allow researchers to distinguish between different branches of the autophagy pathway, which could be particularly useful in translational research.
• This work, published today in Molecular Cell, is dedicated to the late Director of the ����������̳, Michael Wakelam, who contributed to the research before he passed away in March 2020.

The cells in our bodies are always reacting to their changing environment but how do they tailor their response to different encountered stresses? Research published today by members of the Florey lab changes our understanding of the mechanisms used to control autophagy – a key pathway in stress responses - updating current textbook knowledge and providing a new way of distinguishing this pathway in future research.

Through the autophagy pathway, cells constantly recycle materials and dispose of waste molecules. The same machinery controls a range of other vital processes, including immunity and inflammation, through a triggered ‘non-canonical’ function. While it was previously assumed that the same molecular modification of one specific protein (autophagy-related protein 8; ATG8) occurred in both pathways, the team’s latest research has identified an alternative molecular change that distinguishes these closely related, but functionally distinct, autophagy-related processes.

“This discovery is important because it develops our understanding of the basic mechanisms underlying the autophagy pathway,” explained Dr Jo Durgan, a senior postdoctoral researcher in the Florey lab. “This finding is of immediate benefit to researchers interested in discovering more about autophagy, but this type of foundational research may also drive translational, or even therapeutic, developments of the future.”

The researchers’ work brought together scientists from across the Institute’s Signalling research programme, mass spectrometry and lipidomics facilities, along with other academic research organisations, to focus on a specific molecular modification called lipidation – where hydrophobic fat molecules are added to a protein. By analysing the different variations of ATG8 lipidation produced as a result of activating the different autophagy pathways, they were able to identify that a particular phospholipid (phosphatidylserine; PS) is used specifically in the non-canonical autophagy pathway, as well as detecting the established linkage of ATG8 to another phospholipid called phosphatidylethanolamine (PE). Discovering this specific change provides a new and unique molecular signature for studying non-canonical autophagy, and challenges the existing dogma in the wider autophagy field.

A number of different diseases, including cancer and neurodegeneration, have been linked to changes in autophagy function, making it a highly attractive therapeutic target. ATG8 lipidation is widely used to track and assay autophagy. By updating the current understanding of ATG8 lipidation, this new study will help researchers accurately monitor and distinguish between distinct autophagy processes in fundamental and translational research.

This study sits close to the Florey lab’s heart. In reflecting on the research’s timeline from the lab-based work, analysis of the results and dissemination of the research findings, Dr Durgan said: “We finalised this work at a time when the COVID-19 pandemic forced researchers to leave the lab to work from home, move collaborations online and balance extra responsibilities like home schooling.

“This publication feels particularly special as it was finalised during those challenging times. It also brought together many areas of expertise from across the Institute: proteomics, lipidomics, signalling, autophagy, and immunology. This work is dedicated to our friend, colleague and collaborator on this study, Michael Wakelam, who sadly passed away in March 2020.”

Notes to Editors

Publication reference

Florey et al.

"Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine"

Press contact

Honor Pollard, Communications Officer, honor.pollard@babraham.ac.uk 

Image description

Molecular modelling of LC3-PE and LC3-PS in complex with ATG4B.

Affiliated authors (in author order)

Joanne Durgan, senior post doc, Florey group

Katherine Sloan, PhD student, Florey group

Michael I. Wilson, Research Fellow, Hawkins group

Judith Webster, research assistant, Mass Spectrometry facility

Andrea F. Lopez-Clavijo, Head of Facility, Lipidomics facility

Michael J. Wakelam, former Director

David Oxley, Head of Facility, Proteomics Facility

Oliver Florey, Group Leader, Signalling research programme

Research funding

This research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Cancer Research UK, and the Research Council of Norway.

Additional/related resources

Florey lab page

Signalling programme page

News, 19 April 2021, Autophagy experts collaborate to hunt down potential drug targets to tackle neurodegeneration

News, 13 November 2019, How cellular recycling system is put on hold while cells divide

Annual Research Report 2017 feature: The quiet pathway

About the ����������̳

The ����������̳ undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. ����������̳ focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through Institute Strategic Programme Grants and an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.

About BBSRC

The Biotechnology and Biological Sciences Research Council (BBSRC) is part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.

BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.

Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.