Loss of prion protein induces a primed state of type I interferon-responsive genes

The cellular prion protein (PrP(C)) has been extensively studied because of its pivotal role in prion diseases; however, its functions remain incompletely understood. A unique line of goats has been identified that carries a nonsense mutation that abolishes synthesis of PrP(C). In these animals, the PrP-encoding mRNA is rapidly degraded. Goats without PrP(C) are valuable in re-addressing loss-of-function phenotypes observed in Prnp knockout mice. As PrP(C) has been ascribed various roles in immune cells, we analyzed transcriptomic responses to loss of PrP(C) in peripheral blood mononuclear cells (PBMCs) from normal goat kids (n = 8, PRNP(+/+)) and goat kids without PrP(C) (n = 8, PRNP(Ter/Ter)) by mRNA sequencing. PBMCs normally express moderate levels of PrP(C). The vast majority of genes were similarly expressed in the two groups. However, a curated list of 86 differentially expressed genes delineated the two genotypes. About 70% of these were classified as interferon-responsive genes. In goats without PrP(C), the majority of type I interferon-responsive genes were in a primed, modestly upregulated state, with fold changes ranging from 1.4 to 3.7. Among these were ISG15, DDX58 (RIG-1), MX1, MX2, OAS1, OAS2 and DRAM1, all of which have important roles in pathogen defense, cell proliferation, apoptosis, immunomodulation and DNA damage response. Our data suggest that PrP(C) contributes to the fine-tuning of resting state PBMCs expression level of type I interferon-responsive genes. The molecular mechanism by which this is achieved will be an important topic for further research into PrP(C) physiology.