The role of LC3 Interacting Regions in Viral Subversion of Autophagy

Lead Research Organisation: University of Cambridge
Department Name: Pathology

Abstract

Flu can be a very unpleasant illness, but in severe cases it can be life-threatening. I have discovered a way in which the virus that causes flu interacts with one of the body's defence mechanisms called autophagy. Autophagy (literally self-eating) usually provides nutrients to cells when they are under conditions of starvation by recycling internal parts of the cell. This has been adapted for self-defence, so invading bacteria can be targeted to this recycling mechanism. Unfortunately most viruses seem not to be susceptible to this, and some viruses like flu even seem to benefit from autophagy.

The way we discovered that flu was interacting with autophagy was by looking in the virus for a particular binding region that we know usually interacts with an autophagy protein. We have found similar regions in other viruses, and it seems that both Herpes virus and the very dangerous Ebola virus may do the same thing. We therefore propose to try and unravel the details of how the flu virus subverts the autophagy defense mechanism, and also to discover if other viruses use a similar strategy. This could be helpful therefore for advancing our understanding of a lot of different viral diseases, and might lead to better vaccines or antiviral drugs in the future.

Technical Summary

The molecular mechanisms by which viruses subverts autophagy remain largely unknown. I have discovered that binding of the C-terminus of the Matrix 2 (M2) to ATG8-like molecules occurs via LC3-Interacting Region (LIR), and have shown that this has a role to play in viral stability, filament formation and presumably therefore the critical step in the viral life-cycle of transmission between hosts. The M2 LIR also seems to mediate a process by which the plasma membrane becomes LC3 positive, a phenomenon which we describe for the first time. The utilization of a LIR to subvert autophagy by a virus may be a widespread viral strategy, as an accessory matrix protein of Ebola and a type II membrane protein of HSV also appear to contain a LIR motif. This project will explore these convergently evolved strategies in an effort to understand better the way in which these important human pathogens interact with the cell; exploiting technologies recently developed in the host institutions.

Planned Impact

The research planned is investigating the molecular mechanisms by which many viruses potentially subvert a host defence mechanism. This will be of direct benefit to immunologists, virologists and cell biologists. As well as developing new lines of research, there may be important discoveries that will guide therapy for multiple viruses, including discovering potential drug targets and aiding the design of vaccines. It is clearly significant that the principal viruses which will be investigated are important human pathogens. Influenza pandemics claim many lives, and the highly deadly nature of filoviruses such as ebola means their capacity to cause harm is immense. Therefore although the timescales on which the likely benefits will be obtained are relatively long (probably from 5 years to decades), they have the potential to be important for human health on a global scale.

In economic terms, the development of new technologies raises the possibility of patenting some aspects of this research. I have a personal track record of doing this where appropriate, and the institutions in which I plan to work are well set up to support such initiatives. This may have a positive economic impact for the UK. The acquisition of skills pertaining to new technologies developed overseas and brining that expertise back to the UK biomedical community also has the potential to stimulate future research and consequently economic growth.
 
Description Clinician Scientist Group Leader programme.
Amount £2,000,000 (GBP)
Funding ID Francis Crick Institute intramural funding, value of award is approximate. 
Organisation Francis Crick Institute 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 01/2025
 
Description Universal cells to overcome HLA barriers in regenerative medicine.
Amount £823,632 (GBP)
Funding ID MR/S02090X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 01/2022
 
Description Economist Podcast on COVID19 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact You can listen to it here: https://podcasts.apple.com/gb/podcast/babbage-fighting-the-virus/id151230264?i=1000468138613
Year(s) Of Engagement Activity 2020
URL https://podcasts.apple.com/gb/podcast/babbage-fighting-the-virus/id151230264?i=1000468138613
 
Description LRB Article on COVID-19 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact LRB Article widely cited.
Year(s) Of Engagement Activity 2020
URL https://www.lrb.co.uk/the-paper/v42/n06/rupert-beale/short-cuts