molecular and functional characterization of EmergiNG INflammasomES

Project Information

ENGINES

Grant agreement ID: 101018672

DOI

10.3030/101018672

EC signature date 13 August 2021

Start date 1 September 2021

End date 31 August 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 372 637,00

EU contribution

€ 2 372 637,00

Coordinated by

LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Germany

Periodic Reporting for period 2 - ENGINES (molecular and functional characterization of EmergiNG INflammasomES)

Reporting period: 2023-03-01 to 2024-08-31

Summary of the context and overall objectives of the project

Inflammasomes are critical components of the immune system, serving as internal surveillance mechanisms that detect pathogens and monitor cellular health. Although our understanding of these systems is advancing, there are still gaps in our knowledge of how they detect and respond to pathogenic threats at the molecular level.

Recent studies have shed light on two specific types of inflammasome sensors, NLRP1 and CARD8. These sensors are unique in their actions and highly variable across species. Interestingly, NLRP1 has been identified as particularly adaptive in primates, highlighting its evolutionary importance. A landmark discovery revealed that human NLRP1 can directly detect dsRNA, a molecular hallmark of viral infection, positioning it as a critical component of antiviral defense.

To build on these findings, our research project aims to delve deeper into the functions of NLRP1 and CARD8 using advanced methods in functional genomics, proteomics and chemogenomics. The goal is to map the signaling pathways leading to these inflammasomes and to understand their structures and functional mechanisms using cell biology, biochemistry and structural biology techniques.

In addition, by testing different pathogens and using innovative humanized mouse models, we will investigate how NLRP1 and CARD8 contribute to the immune response against infections and maintain the immune cell balance. This comprehensive approach is expected to not only improve our understanding of inflammasome biology, but also pave the way for novel therapeutic strategies to treat disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our group has made significant progress in elucidating the NLRP1 and CARD8 inflammasomes. This includes a more detailed mechanistic understanding of how the NLRP1 inflammasome is activated in response to various stress signals. In particular, we contributed to a pivotal study led by Franklin Zhong's lab that revealed how exposure to harmful UV irradiation or certain toxins triggers a specific cellular process. This process involves post-translational modification of the NLRP1 protein by kinases, which is an important checkpoint in NLRP1 activation. Such findings are critical because they improve our understanding of diseases in which the body's response to environmental stress is impaired, including certain skin conditions and respiratory diseases.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Although not originally part of our research plan, we also made important discoveries about the NLRP3 inflammasome, another key player in the body's defense against infection and control of inflammation. Our findings indicate that the NLRP3 inflammasome requires two steps to become fully operational: first, it is primed to be activated, and then it is activated to trigger a signaling response. Specifically, we discovered that a protein kinase called IKKβ, which is activated during the priming step, helps NLRP3 move to the Golgi apparatus, a special compartment of the cell where NLRP3 can be activated more quickly. Interestingly, another protein called NEK7, previously thought to be essential for this process, was found to be redundant when IKKβ was able to perform its function effectively. This newly identified pathway, observed in human immune cells, appears to be a primary means by which human immune cells use NLRP3 to respond to threats. This suggests that the way NLRP3 prepares to defend the body is more flexible than previously thought.

In the next funding period, we expect significant progress in the molecular characterization of the NLRP1 inflammasome, especially with regard to the biochemical and structural aspects. Our research will aim to understand its response to various stress signals. By using advanced biochemical techniques and structural analysis methods, we aim to uncover the mechanisms of how different cellular stress conditions are integrated by the NLRP1 inflammasome. This work will improve our understanding of the biology of the inflammasome and may identify potential therapeutic targets for inflammatory diseases.