Claudio Joazeiro: “Our knowledge about protein quality control will lead to new ways to approach cancer, neurodegeneration and aging”

Claudio Joazeiro, at the National Cancer Research Center (CNIO). / Laura M. Lombardy. CNIO

Claudio Joazeiro (Brazil, 1968) studies how cells control the quality of their proteins. He wants to find out how cells know when proteins are aberrant or damaged, and how they decide on ways to either correct or eliminate them. “Protein quality control is critical to ensure cellular fitness”, he explains. “Defective protein quality control is a hallmark of neurodegenerative diseases”.

Joazeiro is Full Professor at Heidelberg University (Germany), while keeping a fractional appointment at the Scripps Research in San Diego (U.S). He has recently visited the Spanish National Cancer Research Center (CNIO), invited by the head of CNIO Genomic Instability Group, Oscar Fernández Capetillo. Here he talks about a key cellular machinery involved in protein quality control, the Ribosome-Associated Quality Control (RQC) complex. Joazeiro’s research on mutations affecting this complex are leading to insights onto the molecular basis of Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases, as well as to potential therapeutic targets.

Why is protein quality control such an important process in our cells?

Aberrant proteins are continuously produced as a consequence of, for example, gene mutations, errors during gene expression or chemical damage. Therefore, cells have a variety of protein quality control mechanisms that detect the production of aberrant proteins and prevent their accumulation. Defects in protein quality control are associated with various diseases and are a hallmark of neurodegeneration3.

You discovered Ribosome-Associated Quality Control (RQC), one of those protein quality control mechanisms.

Protein surveillance must occur with great sensitivity and precision, to detect as many forms of protein aberration as possible. RQC is indeed a process that checks the quality of newly made proteins. Ribosomes are the cellular machineries that make new proteins, but for different reasons this process can go wrong, and end up producing proteins that are incomplete, or have other forms of aberration. So, cells need checkpoint processes to make sure that every step in protein synthesis is going on as it should. We have identified a number of factors that carry out this surveillance for an aberrant situation versus a normal situation.

 Is this a mechanism to help the cell clean itself, or just to find out if something is wrong?

It’s both. It’s a process that will check if something is wrong, and if that is the case, it will eliminate these abnormal proteins. There are many processes involved in checking the quality of every type of macromolecule in the cell, whether they are proteins, mRNA, lipids or DNA, for example. Cells are constantly monitoring the quality of its constituents and looking for ways to either correct the problem, or eliminate the aberrations.

What do cells do with the waste, once they eliminate aberrant proteins? Do they ‘recycle’?

Yes. Cells don’t waste anything, if a protein has to be degraded or eliminated, its components (amino acids and short peptides) are recycled.

What were you looking for when you discovered the Ribosome-Associated Quality Control?

We found a new mutation that caused an Amyotrophic Lateral Sclerosis (ALS)-like phenotype in mice: the animals lose motor neurons and develop paralysis. We managed to identify the gene whose mutation causes the problem, but then we wanted to know what it does when it is not mutated. To make a long story short, we found that the protein encoded by this gene is involved in ribosome quality control.

What is the significance of these findings?

First, there is this clear disease relevance: we know that mutations in the pathway cause neurodegeneration. In addition to these mice that I mentioned already, we have found mutations in other components of the RQC system that also cause neurodegeneration in mice, as well as neuromuscular disease in humans. Biologically it is also a very important cellular mechanism. We know that because it has been conserved through evolution: all cells, from bacteria to humans, use ribosome quality control.

 What is the state of the art of your investigation in this field?

The field for the past decade has been very mechanistic, we have identified the factors and the processes that are responsible for this quality control, but now we are integrating this knowledge into biology and disease. We are investigating the role of RQC in neurodegeneration and in cancer, and we want to know what is happening in normal biology, for example in aging or under conditions of nutrient starvation.

What can you tell us about the recent realization that aberrant proteins trigger a complex alarm response in the cell?

What we knew until recently was that RQC eliminates the aberrant proteins, and also the mRNA that was being translated to generate these aberrant proteins. Now we know a lot more. We know that RQC also activates a number of stress-signaling responses, it promotes an overall inhibition of translation in the cell, and it can promote apoptosis [programmed cell death]. It can also promote innate immunity, and all kinds of alarm systems used by the cell to signal that something is going wrong.

How do you see your field in the future?

I think we will be able to modulate the RQC mechanism therapeutically. The ribosome is the cell machinery responsible for making new proteins. It reads the blueprint for a certain protein on a messenger molecule – known as messenger RNA (mRNA) – and then converts this information into new proteins. When this process fails, the ribosome gets stalled on the mRNA and protein synthesis is brought to a halt. I am a believer that if we are able to modulate or to decrease ribosome stalling, we may be able to decrease the rate of aging, for example, and we may find ways to approach cancer therapeutics and certainly neurodegeneration.

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