Bénédicte Py defines the inflammasome

Bénédicte Py, leader of a team at the International Center for Infectiology Research, Lyon, studies the molecular mechanisms that control the triggering of inflammation and are involved in inflammatory diseases. In 2013, she obtained funding from the European Research Council (ERC Starting Grant) to pursue her research.

Inflammasome: a truly awful word, which has never impressed Bénédicte Py. Currently an Inserm Research Fellow at the International Center for Infectiology Research, Lyon (CIRI), she has focused on it since completing her post-doc at Harvard in the United States. “The inflammasome is a big protein complex, assembled in cells in response to certain signals. It controls the triggering of an inflammatory response by secreting pro-inflammatory cytokines,” she explains. It can be activated by several stress receptors, including the NLRP3* receptor, which is central to my research.”

NLRP3, a receptor activated in several common chronic diseases

This protein was discovered in 2001, following genetic analyses conducted in patients with hereditary autoinflammatory diseases. It works as a sensor that can detect a problem in the body. “It is sensitive to numerous stimuli: bacteria, viruses and fungi, as well as inhaled crystalline structures such as silica or asbestos. Furthermore, it is active in chronic diseases with an inflammatory component, such as diabetes or atherosclerosis,” she explains. Despite these observations, researchers still know little about how it works and how it is regulated. And this is where Bénédicte Py is trying to break new ground.

“During my post-doc, we identified small molecules that can inhibit NLRP3, and characterised their mechanisms of action. We then discovered that NLRP3 activation was controlled through its binding to ubiquitin, a small protein present in all cells, which binds to other proteins in order to modify their properties. This raised questions on regulation, on the consequences of this ubiquitination for NLRP3 conformation, and on the possible involvement of these biochemical modifications in certain diseases,” explains the researcher. 

Decoding the mechanisms of this activation

Following this work, while she was a lecturer at Lyon 1 University, Bénédicte Py therefore decided to apply to the European Research Council for funding: “I wanted to go further: to dissect and discover the mechanisms behind NLRP3 activation. Where is this protein, and what is its resting form? What happens when it is activated?" The proposal won over the jury, who awarded her €2 million over five years to carry out her work. There are probably two reasons for this outcome, reckons the researcher: “NLRP3 is involved in many diseases with a high prevalence, such as diabetes, cancer, Alzheimer's disease or atherosclerosis. Diseases in great need of therapies. The mechanism of NLRP3 activation is a real black box on which we have very little knowledge.”

Since then, things have really taken off. The year after she obtained this funding, she was recruited by Inserm to pursue her project. “Having this project and funding has certainly contributed to this recruitment,” she acknowledges. She then put together her team, currently comprising seven people. “This prize has been a tremendous opportunity. Apart from the fact that it gives me visibility for my work in the medium term, it has contributed to strengthening my network and collaborations, particularly in France and in Europe. It is a business card that has led to invitations to several conferences, and given me a chance to meet people who are important to my work,” she explains.

Several articles are in preparation: “We have very promising initial results. This takes time, because we are generating several transgenic mouse models to validate our hypotheses in vivo. Time is running out and we are already starting to apply for funding to continue!

Note:

*nucleotide-binding domain, leucine-rich repeat and pyrin domain containing 3

Find out more about Bénédicte Py and her work
Bénédicte Py leads the Inflammasome NLRP3 team at Inserm/CNRS/ENS/Claude Bernard University Unit 1111, at the International Center for Infectiology Research, Lyon.

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