What is the problem/issue being addressed?
The immune system coordinates responses against plethora of pathogens thanks to messenger molecules and cell surface proteins that serve as antenna. These proteins rely on the secretory pathway to be traffic them around and out of the cell. How cells exert this crucial activity is largely unclear, and a major problem in understanding immunity.
The advances in this field of research is hampered by a major problem represented by the lack of knowledge on the molecular interactions occurring with and around protein traffic in the cell. Rhomboid-like proteins are critical fate determinants of protein traffic, however we lack fundamental understanding of their interactions at molecular level. This project aims to tackle this problem by investigating with two paradigmatic proteins in this superfamily, namely RHBDL4 and iRhom2, at fundamental mechanistic cell biological level and from the physiological-immunological point of view. Any discovery in such context would enormously expand our knowledge of the processes where these two proteins are involved, including the immune system. Therefore, I aim in this project to expand our understanding of molecular interactions of RHBDL4 and iRhom2 by using a biochemical screen to identify potential interactor proteins. This should allow large expansion of mechanistic studies over the function of these two members of the rhomboid-like proteins. Importantly, the same approach could be used for other members of the rhomboid-like proteins, thus initiate a new intense expansion of our knowledge of the processes that involve rhomboid-like proteins.
Why is it important for society?
Rhomboid-like proteins are important regulators of protein traffic in the cell. Most diseases show abnormal protein traffic, and understanding how these regulators function could open the doors to the cure of a vast number of diseases. For example, iRhom2 regulates the traffic of an enzyme critical for the secretion of TNFalpha, a potent immune and inflammatory factor released chronically in rheumatoid diseases. Currently available cure is expensive injections with antibodies capable of neutralising TNFalpha. A design of a drug interfering with molecular interaction and thus inhibiting the release of this factor could reduce enormously the costs of treatment of a common disease in the European Union.
Moreover, RHBDL4 and iRhom2 are paradigms of two types of rhomboid-like proteins: the small enzymatically active rhomboids and the large catalytically inactive pseudo enzymes. Comparing these very different proteins can shed light on conceptual aspects of how this superfamily of proteins function. This becomes important in understanding other members of the superfamily, for example of rhomboid-like proteins of pathogens such as Toxoplasma gondi, Trypanosoma brucei, Mycobacterium tuberculosis. Finally, a number of virus such as Human Immune deficiency virus (HIV) causing acquired immune deficiency syndrome (AIDS), is known to highjack protein traffic within cells using the processes where RHBDL4 and iRhom2 and involved.
What are the overall objectives?
The main objective of the project is to identify molecular interactions of two proteins belonging to the superfamily of rhomboid-like proteins, RHBDL4 and iRhom2, and understand the physiological and cell biological relevance of these interactions. Finally the project aims to dissect at the mechanistic level the role of these proteins in the immune system.
