This is an R21 proposal to investigate Phospholipase D4 (Pld4) a novel gene of unknown function with homology to classical PLD enzymes. Pld4 has been linked to inflammatory and autoimmune diseases. We generated a conditional knockout allele of Pld4, Pld4 monoclonal antibodies, and Pld4-mutated cell lines using CRISPR to study Pld4 expression and function. Pld4-/- plasmacytoid dendritic cells were found to have defects in type I interferon and other cytokine responses to endocytosed nucleic acid ligands. The present proposal explores several hypotheses related to how Pld4 might function in pDCs and other leukocytes to facilitate these responses. The immediate goal is to understand how Pld4 functions in pDCs and other leukocytes. Long-term goals are to understand all of the roles of Pld4 in health and disease and to explore whether Pld4 might be a good target for therapeutic intervention, particularly in autoimmune disease or vaccinology.
We recently generated mice carrying a mutation in the poorly characterized Pld4 gene and found that these mice have severe dysregulation of the interferon response, probably because of defects in nucleic acid sensing by plasmacytoid dendritic cells. Because this pathway has been implicated in both viral resistance and the promotion of autoimmune disease, elucidation of the functions of the Pld4 protein might allow new treatments of human disorders by facilitating development of drugs that block or enhance its function. To approach this, we will determine more precisely how Pld4 functions in this response.
| Gavin, Amanda L; Huang, Deli; Huber, Christoph et al. (2018) PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nat Immunol 19:942-953 |
