Inflammation and cancer: Sharpin at the sharp end

Professor Henning Walczak and his team have made an important discovery about inflammation.

It’s taken six years, the development of a new experimental technique and a move from Germany to London, but an international team of scientists, including some funded by Cancer Research UK, have finally uncovered a vital piece in the scientific puzzle that links inflammation to diseases such as cancer and arthritis.

Publishing their results in Nature this week, Professor Henning Walczak‘s team at Imperial College London describe how a protein called Sharpin helps to switch between ‘good’ signals in cells – which are important for responding to disease – and ‘bad’ signals, which lead to inflammation and cell death.

Here’s a short audio clip of Professor Walczak discussing his new research – and below that, our in-depth analysis of what the researchers found:

Link to transcript

The two faces of TNF

The story focuses on Tumour Necrosis Factor (TNF) – a protein we’ve previously written about on the blog. It plays a central role in our body’s immune system, helping to control inflammation – the reddening and swelling that happens as our body responds to damage or infection.

A certain amount of inflammation is a good thing – it helps to recruit white blood cells to the area to fight off any invading infection, and it also kick-starts the healing process by increasing blood flow to the area.

But too much inflammation can be troublesome, as long-term inflammation has been implicated in the development of some cancers. And uncontrolled inflammation of healthy body tissues lies at the heart of auto-immune diseases such as rheumatoid arthritis, psoriasis and more.

Normally, our immune cells produce TNF in response to infection. It’s a ‘messenger’ molecule that sends signals to immune cells and other tissues, switching on a flurry of gene activity that helps to drive inflammation and healing.

But the molecule has a darker side to its character. As well as activating ‘good’ processes that help fight infection, TNF can switch on so-called ‘necrotic cell death’, leading to unwanted inflammatory responses and auto-immune diseases. It’s this dark side of TNF that may also be involved in cancer, by causing the chronic inflammation that increases the chances of the disease developing and helps established tumours to spread.

Over the years, scientists around the world have been studying how TNF sends signals to the immune system, yet it’s still not really clear what flips it from being a ‘good guy’ to a ‘baddie’. But the new results from Professor Walczak and his team provide a major clue as to what’s going on.

Finding the Sharpin switch

Our cells are like a bustling city, packed with busy workers in the form of proteins. And just as employees have to work together in teams, proteins team up to do various jobs. Some are in administration, helping to switch genes on and off, while others are involved in construction, communication, waste disposal and dozens of other specific roles.

To figure out the members of the protein ‘team’ responsible for switching TNF from good to bad, Professor Walczak and his colleagues had to develop a new and highly sensitive technique, which purifies and identifies proteins that are closely associated and interact together in cells.

Using their new technique, the researchers studied the group of proteins that come together to enable TNF to send signals within immune cells, and discovered that a protein called Sharpin was a member of the TNF signalling team.

Sharpin is already known to scientists – it’s been found to play a role in sending signals in the brain. And mice with a faulty version of the gene have problems with inflammation and dermatitis.  But what exactly was Sharpin doing in the TNF team?

Further tests showed that Sharpin builds short chains of a molecule called ubiquitin- a kind of molecular label to mark a wide variety of proteins. For example, ubiquitin labels may mark proteins out to be destroyed, or to be modified in some way.

Next, the scientists wanted to know whether these ubiquitin chains were involved in TNF signalling. Working together with colleagues in Australia, they developed an even more sensitive version of their protein identification technique. This revealed that vital components of the TNF ‘team’ (known more correctly as the TNF signalling complex) had been tagged with ubiquitin labels. But was Sharpin responsible?

Closing the loop

To find out, the researchers studied skin cells from mice lacking Sharpin. These animals have an inflammatory skin condition called chronic proliferative dermatitis.

The scientists discovered that without Sharpin, the skin cells didn’t respond properly to TNF signals – instead of switching on the ‘good’ genes that help to fight infection and heal, they activated the ‘bad’ genes that fire up chronic inflammation and cell death.

As a final test, the team looked at skin cells from mice lacking both Sharpin and TNF. Instead of the inflammation problems the scientists expected, the cells were fine. This result suggests that it must be TNF causing the ‘bad’ inflammation problems in the mice without Sharpin. And when the scientists treated these skin cells with TNF in the lab, they saw the classic hallmarks of uncontrolled inflammation.

Piecing together the picture

Together, these results show that Sharpin plays a crucial role in keeping TNF under control, steering it towards driving healthy inflammation and away from the ‘dark side’ by labelling it with ubiquitin. In the absence of Sharpin’s controlling influence, TNF – and therefore inflammation – runs amok.

Not only is this discovery interesting from a purely scientific point of view (it’s a pretty significant discovery in the field of immune signalling) but it sheds light on a range of diseases. Inflammation is a key factor in auto-immune diseases, such as arthritis, Crohn’s disease, lupus and psoriasis.

And, as we’ve mentioned, inflammation is also implicated in cancer developing and spreading. If we can understand more about the molecules that drive inflammation – such as TNF and Sharpin – it may provide vital leads for new ways to treat or even prevent cancer, as well as other diseases.

At the moment, this research is still at an early stage in the lab. Although it’s too soon to start thinking about how this discovery could be used to treat patients right now, it’s another important step forward for tumour biology.

But getting a grip on the fundamental molecular processes that underlie cancer, such as inflammation, is the foundation on which we build future treatments for the disease.

Kat

Reference:
Gerlach, B. et al (2011). Linear ubiquitination prevents inflammation and regulates immune signalling Nature, 471 (7340), 591-596 DOI: 10.1038/nature09816