TRIM21 and antibody immunity

Scientists from MRC Laboratory of Molecular Biology (LMB) and the Max Planck Institute for Biophysical Chemistry recently developed a method called Trim-Away, which makes it possible to directly target almost any protein in any type of cell.

The method involves TRIM21, a protein discovered at Dr James’s lab at the MRC LMB. The protein recognises antibodies that enter the cell attached to viruses. It binds to these antibodies, tags the antibody-virus-complex as ‘garbage’ and hands it over to the cell’s ‘garbage chute’, the proteasome.

Dr James, who classifies himself as a host-pathogen biologist, is one of the speakers at the 44th Lorne Conference on Protein Structure and Function, to be held at Lorne Cumberland from 10–14 February, 2019. Here, he talks about host-pathogen interaction and TRIM21. 

What’s your lab’s current research focus?

The relationship between hosts and pathogens is fascinating because of the endless evolutionary struggle between the two, as first one and then another seeks an advantage. Viruses relentlessly evolve unexpected and ingenious ways to exploit their host, while hosts have to continuously match these schemes with stratagems of its own. The resulting evolutionary battle has been described as the ‘Red Queen Paradox’ after the conversation between Alice and the Red Queen (from Lewis Carroll), who said: “it takes all the running you can do to say in the same place”. 

One current focus of my lab is a protein called TRIM21, which we discovered a few years ago is a cytosolic antibody receptor. Our discovery was unexpected because until this time it was always thought that antibodies function exclusively outside of cells. What we were able to show is that, during infection, viruses enter our cells with antibodies attached to their surface. Once inside the cell, TRIM21 detects each virus via their associated antibodies and alerts the host that it is under attack. What is particularly cool about TRIM21 is that it both raises the alarm and attempts to destroy the virus immediately. TRIM21 can do this because, as well as being an antibody receptor, it is also a highly efficient enzyme that catalyses a process called ubiquitination. TRIM21 uses ubiquitination to label viruses for degradation by the cell’s recycling machinery, such as the proteasome, thereby preventing infection.

Can you please share your Eureka moment with our readers?

I would say the discovery of this hidden world of intracellular antibody immunity, mediated by TRIM21, was definitely my Eureka moment. It was unexpected because our view of antibodies as purely extracellular had been held for over a century. Remarkably, it turns out that TRIM21 is actually the highest affinity (most efficient) antibody receptor in humans and is expressed in almost every cell in our body. It’s been protecting us from infection for millions of years and we didn’t even realise it was there.

The cool thing about TRIM21 is that it works against anything with an antibody stuck to it — this makes it effective against a broad range of viruses, bacteria and also pathogenic proteins that are the cause of neurodegenerative diseases like Alzheimer’s. We realised early on that we might be able to exploit this activity and get TRIM21 to selectively remove proteins from the cell, as both a research tool and ultimately a powerful therapeutic. Eventually we were able to get this concept to work in practice, leading to the development of ‘Trim-Away’, which combines electroporation of off-the-shelf antibodies with TRIM21 in order to deplete individual proteins from the cell in less than an hour. Trim-Away works in primary cells as well as cell lines and offers an alternative to siRNA but which works faster and at the protein level. We’d like to extend this concept to make therapeutics and that is part of ongoing work.

What according to you are the top three developments in the field? 

I would say Edward Jenner’s discovery that vaccination protects against infection has had a larger impact on human health than any other research before or since. Subsequent to Jenner, the race to develop the polio vaccine in the 1930s–1950s to my mind is equivalent to, and more important than, the later ‘space race’ and shows what science can achieve with proper encouragement and investment. As these two moments are so pivotal, I’m going to take them as separate achievements and two of the top three! For the final top development, I would say the engineering of therapeutic antibodies by phage display and humanisation. I may be slightly biased because my own work revolves around antibodies, but their use in therapy is now a multibillion-dollar industry, with antibody-based therapeutics now outselling traditional small molecule drugs. The scientist, and recent Nobel Prize winner, who made this possible, Greg Winter, is an ex-director of the LMB and has been inspirational to many of us in the field. 

What are you going to talk about at the 44th Lorne Conference on Protein Structure and Function?

At Lorne, I plan to introduce TRIM21 and provide an overview of how this has changed our understanding of antibody immunity. I will explain why it is important, how it works and how we are exploiting our understanding to develop tools and eventually new therapeutic treatments.  

Figure 1: TRIM21 is the highest affinity antibody receptor in mammals. It intercepts antibody-coated viruses in the cytosol and mediates their proteasomal degradation to prevent infection. TRIM21 has an unusual mechanism of ubiquitination that allows it to target any antibody-bound molecule for degradation, including proteopathic agents such as tau or cellular proteins.