Young Scientists at #LINO22 – Proteins, the Working Bees in the Body

As BBSRC Discovery Fellow at Newcastle University Chiara Maniaci focuses on the functions of ubiquitin-like proteins in the cells. Looking forward to attending the 71^st Lindau Nobel Laureate Meeting, the chemist expects to experience a unique opportunity to meet many outstanding pioneers and young researchers who will shape the future of chemistry.

It has been estimated that the human body contains up to 6 million proteins species, but only around 20,000 have now been identified and characterised. This observation highlights that we have only just scratched the surface in terms of the variety and complexity of our bodies and as such many more proteins are yet to be identified. It is well understood that the number of proteins an organism produces can be several times greater than the number of its genes.

So, how does the cell increase complexity and diversity? One way the cell diversifies its proteome is via „cleave-to-modify“ mechanism. This uses „scissors“ enzymes to cleave progenitor proteins after they are produced in the cell. The released neo-protein fragments may be stable in vivo and acquire neo-functions of biological and therapeutic relevance. But that is not all. Often these neo-proteins are further modified chemically as a way, for example, to switch on and off their acquired neo-functions.

Key Role of the Spliceosome

My current work focuses on shining light on an unprecedented „cleave-to-modify“ mechanism that involves a ubiquitin-like protein, its processing and chemical modification, and how this affects the way the cell determines which proteins are synthesised at what time. In the body, proteins are like working bees. They are responsible for the makeup and proper functioning of cells. They help metabolise and digest our food. They make it possible for the brain to work, and much more.

The instructions necessary for the cell to make a protein are available in the form of encrypted code. Nature has evolved a very clever multi-component cellular machinery called the spliceosome, that is responsible for decrypting this code by removing all the gibberish letters, as such making the message readable.

Because the spliceosome plays such a key role in maintaining a healthy body, cellular mechanisms are in place to make sure the code decryption goes on smoothly, as in the case of healthy cells, and does not go awry, as in disease. It has recently been discovered that there are special scissors that trigger the trimming of some protein components to control the activity of the spliceosome. However, little is known about the identity of such „cellular scissors“, how this process is regulated, and how this affects decrypting the code. My research aims to shine light on this missing piece of the puzzle not only to progress our understanding of how this system works but also to provide an alternative way to treat diseases that are sustained by this very important mechanism.

Missing Piece of the Puzzle

The work of Aaron Ciechanover, Avram Hershko and Irwin Rose, the recipients of the 2004 Chemistry Nobel Prize, was ground-breaking as it revealed how cells control the breakdown of many proteins via a system called the „ubiquitin-proteasome“. This discovery changed our understanding of protein homeostasis, and it has provided the scientific community with important information about how proteins are destroyed inside the cell.

We now also know that ubiquitin has multiple cousins with similar structure, called ubiquitin-like proteins, which are involved in many important processes, from DNA repair to protein trafficking, to the cell cycle. This is an amazing example of how nature renovates the resources it has in hand, something we as human beings are still trying to emulate. Still, there are more molecules and mechanisms out there to be discovered, so we have only barely scratched the surface.

Impact of the Pandemic and a Hopeful Outlook

The pandemic has been a very difficult time for everyone, we all had to adapt to a new reality and find new ways to keep living our lives. For scientists and early career researcher like me, it was extremely hard. I was awarded my fellowship just few weeks before the first lockdown and for almost a year access to the lab was very limited. This had a major impact on the science progress and on getting the preliminary data very much needed to apply for the next grant and secure a permanent position.

Now that hopefully the worst is behind us, I can say that I have learnt a lot during this hard time, for example how to be resilient, think creative and find different and innovative ways to perform experiments, turning a difficult time into something positive and productive. I strongly believe in the power of sharing knowledge and connecting with the community, foster exchange of new ideas, interaction and networking, something that was massively impaired during the pandemic. At the 71^st Lindau Nobel Laureate Meeting, I will be able to enjoy an enriching exchange across generations, cultural and geographical boundaries, fostering future collaborations and cross-pollination of ideas from different areas.