Project description
Investigating the complex role of RNA-binding proteins in RNA stability
CD8+ T cells are essential for the control of infections and tumour cell elimination via inflammatory cytokines and cytotoxic molecules. The production of these effector molecules requires regulation to prevent their malfunction, which can result in life-threatening diseases. The regulation of RNA stability and translation efficiency by numerous RNA-binding proteins (RBPs) remains poorly understood. The EU-funded PRinTERs project will use mouse genetics as well as molecular and cellular biology to study the RBPs' control of cytokine production. Highly sensitive proteomics techniques will identify the RBP repertoire in human T cells, while functional screens will identify those RBPs that control specific effectors. The selected RBPs will be studied for their role in T cell response to infection and tumour formation.
Objective
CD8+ T cells are critical to fight infections and to clear tumor cells through the production of inflammatory cytokines and cytotoxic molecules. These effector molecules must be tightly controlled: too little leads to the inability to control the pathogen, and too much can result in a life-threatening cytokine storm and tissue damage. While transcriptional control of effector genes is well-studied, regulation at the levels of RNA stability and translation efficiency by RNA-binding proteins (RBPs) has remained underappreciated. We recently found that several cytokines are tightly regulated through these processes, and we identified ZFP36L2 as one of the responsible RBPs. However, much is still to be learned about the underlying molecular mechanisms. Moreover, there are >1000 putative RBPs, and a systematic analysis of their regulatory activity in T cells is lacking, particularly with regard to the control of effector proteins.
Here, we will use a combination of mouse genetics, and molecular and cellular biology to gain a deep understanding of the control of cytokine production by RBPs, using ZFP36L2 as a paradigm. Next, we will take a novel, highly sensitive proteomics approach to systematically identify the RBP repertoire in resting and activated primary human T cells. Complementary functional screens will identify those RBPs that control specific effectors. Selected RBPs identified in these screens will be studied in-depth to understand their roles in T cell responses to acute infection and in tumor models. Lastly, we will define how RBPs can imprint and/or maintain the killer phenotype of human CD8+ T cells.
This research will significantly advance our understanding of post-transcriptional regulation of T cell effector activity, and it should help us to develop novel tools to drive effective T cell responses against pathogens and malignant cells.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
1006 AN Amsterdam
Netherlands