The Heit lab is excited to announce the publication of our most recent study, which uses evolution as a tool to investigate the biology of the receptor MERTK.
Every day the normal turnover of cells in our tissues results in the production of around 100 billion dying cells. These dying cells must be removed to keep our tissues healthy. MERTK plays a central role in this process – in fact, MERTK is one of the major receptors used by cells such as macrophages to recognise and remove these dying cells. In humans, defects in MERTK function can lead to many diseases including retinitis pigmentosa – a form of blindness, autoimmune diseases such as multiple sclerosis, heart diseases such as atherosclerosis, and even infertility. Furthermore, viruses such as HIV and Ebola, as well as some cancers, use MERTK to gain access to our cells and to manipulate our immune system. Despite these multiple roles in human health, we still have a poor understanding of how MERTK functions.
In our newest study, currently available as a corrected proof at Molecular Biology and Evolution, we use an evolutionary approach to better understand the function of MERTK. Unexpectedly, we discovered that MERTK has undergone recent positive selection – a form of evolution rarely observed in human genes. Further investigation into this evolution revealed that human MERTK has evolved to be present in smaller amounts on our macrophages than in our ancestors, while simultaneously evolving to self-structure into miniature “islands” on the macrophage surface. While it may seem counter-intuitive to reduce the amount of an important gene expressed by our cells, as this would make the gene less able to do its work, the lower expression decreased the ability of viruses to parasitize MERTK-expressing cells. The increase in MERTK clustering evolved to counteract this decreased expression, through enhancing the avidity of MERTK. Thus, MERTK has evolved to limit the extent to which viruses can parasitize it, and compensates for the reduced levels of MERTK by increasing its avidity.
The evolutionary trend we observed is especially exciting as it is consistent with a form of evolution termed “antagonistic coevolution”, or more commonly referred to as the red queen hypothesis. In this form of evolution, a pathogen and its host become locked in an arms-race, in which advantages gained by evolution of the host are rapidly counteracted by coevolution of the pathogen. The end-effect is a zero-sum change in the interaction between the host and the pathogen – i.e. the host and pathogen still survive, despite being better “armed” to fight each other.
Evolution aside, the observation that MERTK is structured into preformed islands on the cell surface is of great interest, as this type of clustering is often a result of interactions with other proteins. As such, these “islands” may represent a previously unsubscribed interaction between MERTK and some form of human-specific co-receptor. The Heit lab is currently investigating this possibility, in the hopes that by understanding these newly evolved interactions that we may gain further insights into the human diseases caused by MERTK dysfunction.
Reference:
Evans AL, Blackburn JW, Taruc K, Kipp A, Dirk BS, Hunt NR, Barr SD, Dikeakos JD, Heit B. Antagonistic Coevolution of MER Tyrosine Kinase Expression and Function. Mol Biol Evol. 2017 Mar 23. Pubmed ID: 28369510.
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