Project Details
Projekt
The deubiquitinating enzymes CYLD and A20 as gate keepers of central nervous system homeostasis
Applicant
Professor Dr. Ari Waisman
Subject Area
Immunology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500247271
Lysine-63 ubiquitination is a post-translational modification that leads to the activation of the NFkB signaling pathway. Removal of these ubiquitin chains is performed by a class of proteases termed deubiquitinating (DUB) enzymes, representing an important mechanism to control NFkB activity. We and others have shown that the DUB enzymes A20 and CYLD regulate the NFkB pathway in a variety of immune cells, including T cells, B cells, dendritic cells as well as in different macrophage subsets, including particularly microglia cells. We recently reported that A20 plays a critical role in the function of microglia during steady state, where in the absence of A20, the microglia started to express genes associated with viral infection, which ultimately led to the invasion of the CNS by CD8+ T cells. Furthermore, mice lacking A20 in microglia presented with dysfunctional neuronal networks, which could be corrected by the elimination of the invading T cells. We have recently also generated mice that allow for the tissue-specific deletion or overexpression of CYLD. Preliminary data obtained with these mice shows that CYLD overexpression results in reduced entry of lymphocytes to the CNS during steady state. Furthermore, deletion of CYLD in microglia leads to increased invasion of the CNS by T cells, thus suggesting that CYLD and A20 may play a similar role for microglia function. In the frame of this grant proposal, we plan to further investigate the precise role of CYLD during microglia homeostasis. In addition, we want to test the different mice with microglial DUB mutations in a model of CNS autoimmunity in order to decipher the role of microglia in promoting pathogenic T cell responses and the possible contribution of dysregulated NFkB signaling in these processes. Finally, we aim to analyze the possible role for the investigated DUB enzymes in the process of ageing, using both mouse models and human post mortem material from healthy (aged) as well as Alzheimer’s Disease patients. Together, our proposed experiments aim to evaluate A20 and CYLD as potential regulators of microglia activity and function at steady state as well as during CNS inflammation associated with autoimmunity or ageing.
DFG Programme
Priority Programmes
