Final Report Summary - IPAD (Intramembrane Proteases, their Inactive cognates, and Disease)
Publishable Summary.
The ability of cells to communicate with one another is essential for all aspects of multicellular life. In animals, this includes growing or repairing tissues, the proper functioning of the immune system, and control of metabolic homeostasis. Signaling proteins are produced in a cellular compartment called the endoplasmic reticulum, then have to be trafficked to the cell surface, from where signaling occurs. One third of all proteins produced by the cell pass through this route—which is called the ‘Secretory Pathway’. This project aimed to understand how trafficking of proteins within the secretory pathway affects the ability of cells to relay signals and in turn, how this impacts on disease. During this period, our work has been published in 6 international, peer-reviewed manuscripts. Below I describe the major research highlights of the program.
One of our major aims was to elucidate how a family of membrane proteins called iRhoms regulate intercellular signaling. Our previous work identified that iRhom proteins which control the tranfficking of a protease called ADAM17 (also called TACE) from the endoplasmic reticulum to the cell surface. On the cell surface, ADAM17 cleaves important signaling molecules, enabling their release from cells and hence ability to trigger signaling in neighbouring cells. Important signaling proteins cleaved by ADAM17 (i.e. substrates) include the key inflammatory cytokine TNF (tumour necrosis factor), which is central to the pathogenesis of infectious and inflammatory diseases (e.g. arthritis, inflammatory bowel disease). ADAM17 also cleaves a range of other molecules, including growth factors, that promote the proliferation of tumour cells.
During the period of the project, my lab made two major discoveries on how the iRhom/ADAM17 pathway is regulated. First, we found that iRhoms are central to the mechanism whereby inflammatory or growth-promoting stimuli activate ADAM17. We found that iRhoms exist in an inhibitory complex with ADAM17 on the cell surface, which prevents ADAM17 from cleaving its substrates. In the presence of activating signals, iRhom proteins undergo an important modification which triggers iRhom to release ADAM17, unleashing its ability to cleave signaling molecules. A second major success was to identify a novel protein that we have named iTAP which binds to and regulates iRhom proteins to control ADAM17 activity. Our work shows that iTAP controls the trafficking of the iRhom/ADAM17 complex to the cell surface. When iTAP is silenced, both proteins are mis-trafficked to the wrong cellular location and TNF cannot be released from cells. A third and unexpected discovery is our finding that iRhom proteins play a central role in signaling events that mediate metabolic control. We find that mice in which the iRhom2 gene is knocked out, are protected from a range of co-morbidities associated with obesity, including insulin resistance, weight gain and the development of fatty liver disease.
In summary, our work identifies novel regulatory mechanisms likely to play an important role in controlling the pathogenesis of inflammatory disease, cancer or obesity and its co-morbidities. We hope that this information can later be exploited in pharmacological settings for the treatment of human inflammatory disease, cancer or metabolic diseases. Lab website: www.igc.gulbenkian.pt/cadrain.
The ability of cells to communicate with one another is essential for all aspects of multicellular life. In animals, this includes growing or repairing tissues, the proper functioning of the immune system, and control of metabolic homeostasis. Signaling proteins are produced in a cellular compartment called the endoplasmic reticulum, then have to be trafficked to the cell surface, from where signaling occurs. One third of all proteins produced by the cell pass through this route—which is called the ‘Secretory Pathway’. This project aimed to understand how trafficking of proteins within the secretory pathway affects the ability of cells to relay signals and in turn, how this impacts on disease. During this period, our work has been published in 6 international, peer-reviewed manuscripts. Below I describe the major research highlights of the program.
One of our major aims was to elucidate how a family of membrane proteins called iRhoms regulate intercellular signaling. Our previous work identified that iRhom proteins which control the tranfficking of a protease called ADAM17 (also called TACE) from the endoplasmic reticulum to the cell surface. On the cell surface, ADAM17 cleaves important signaling molecules, enabling their release from cells and hence ability to trigger signaling in neighbouring cells. Important signaling proteins cleaved by ADAM17 (i.e. substrates) include the key inflammatory cytokine TNF (tumour necrosis factor), which is central to the pathogenesis of infectious and inflammatory diseases (e.g. arthritis, inflammatory bowel disease). ADAM17 also cleaves a range of other molecules, including growth factors, that promote the proliferation of tumour cells.
During the period of the project, my lab made two major discoveries on how the iRhom/ADAM17 pathway is regulated. First, we found that iRhoms are central to the mechanism whereby inflammatory or growth-promoting stimuli activate ADAM17. We found that iRhoms exist in an inhibitory complex with ADAM17 on the cell surface, which prevents ADAM17 from cleaving its substrates. In the presence of activating signals, iRhom proteins undergo an important modification which triggers iRhom to release ADAM17, unleashing its ability to cleave signaling molecules. A second major success was to identify a novel protein that we have named iTAP which binds to and regulates iRhom proteins to control ADAM17 activity. Our work shows that iTAP controls the trafficking of the iRhom/ADAM17 complex to the cell surface. When iTAP is silenced, both proteins are mis-trafficked to the wrong cellular location and TNF cannot be released from cells. A third and unexpected discovery is our finding that iRhom proteins play a central role in signaling events that mediate metabolic control. We find that mice in which the iRhom2 gene is knocked out, are protected from a range of co-morbidities associated with obesity, including insulin resistance, weight gain and the development of fatty liver disease.
In summary, our work identifies novel regulatory mechanisms likely to play an important role in controlling the pathogenesis of inflammatory disease, cancer or obesity and its co-morbidities. We hope that this information can later be exploited in pharmacological settings for the treatment of human inflammatory disease, cancer or metabolic diseases. Lab website: www.igc.gulbenkian.pt/cadrain.