Crossroads of immunometabolism and human immunodeficiency

Human cells depend upon proteostasis; a collective term used to describe the processes that ensure the accurate production of all the necessary proteins required for cells to function and respond to their environment. Such is the importance of proteostasis, cells possess various elegant and highly sophisticated molecular strategies that allows them to rapidly adjust proteostasis when responding to stressful signals coming from either inside or outside the cell. The major place where proteostasis control occurs is within a cellular compartment called the endoplasmic reticulum (ER). Despite major advances in our understanding of the ER, there is still much to be learnt about the molecular basis of proteostasis control and how impairments in proteostasis management cause cell dysfunction and contribute to human disease. In this project we investigate patients with a severe immunodeficiency disease caused by a single change in their DNA at a specific location that results in their cells not being able to produce a particular protein that is normally found only within the ER. Based upon what little information is known about this protein, we believe it is critical for the control of proteostasis. We will therefore comprehensively study the blood immune cells from these patients to discover the real function(s) of this molecule in proteostasis control in both the healthy setting and how its deficiency causes immune dysregulation. Our results so far have revealed that B cells, a type of immune cell responsible for the production of antibodies key circulating molecules that provide immune protection, are particularly sensitive to the breakdown of proteostasis greatly reducing their cellular survival. Furthermore, in another important immune cell, T cells, the loss of proteostasis control led to these cells being fatigued which was associated with a lowered metabolic capacity. Therefore, we plan to delve deeper into understanding proteostasis control in the human immune system by applying sensitive newly developed tools to probe defective proteostasis and ER biology as well as modern state-of-the-art facilities to map the altered metabolic pathways and cell dysfunction. Cutting-edge molecular techniques will allow us to identify additional molecular partners of potential relevance that might contribute to our patients disease. Lastly, after combining this newly formed data, with existing currently available information we will apply computational modelling to predict further candidate proteins whose dysfunction might also cause a similarly damaging immunodeficiency disease. We expect that this work will undoubtedly further our understanding about proteostasis control in the human immune system and uncover important reciprocal links with cellular metabolism.