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

• DOI: 10.1371/journal.pone.0179881
• Publication Date: 2017-06-26T13:42:26Z
• Authors: Giulia Malachin; Malin R. Reiten; Øyvind Salvesen; Håvard Aanes; Jorke H. Kamstra; Kerstin Skovgaard; Peter M. H. Heegaard; Cecilie Ersdal; Arild Espenes; Michael A. Tranulis; Maren K. Bakkebø
• Keywords: Male; DRAM1 gene; peripheral blood mononuclear cell; genotype; limit of quantitation; OAS1 gene; Gene Expression; animal cell; DNA damage response; immunomodulation; transcriptomics; Gene Knockout Techniques; Mice; Leukocytes; ISG15 gene; DDX58 gene; 0303 health sciences; messenger RNA; Goats; Q; apoptosis; article; R; interferon; protein function; female; Interferon Type I; MX1 gene; Medicine; Female; protein RNA binding; Research Article; 570; phenotype; Science; RNA sequence; Cell Line; 03 medical and health sciences; male; Animals; Humans; controlled study; PrPC Proteins; gene; protein expression; Homeodomain Proteins; MX2 gene; nonhuman; protein depletion; Gene Expression Profiling; cell proliferation; OAS2 gene; prion protein; upregulation

The cellular prion protein (PrPC) 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 PrPC. In these animals, the PrP-encoding mRNA is rapidly degraded. Goats without PrPC are valuable in re-addressing loss-of-function phenotypes observed in Prnp knockout mice. As PrPC has been ascribed various roles in immune cells, we analyzed transcriptomic responses to loss of PrPC in peripheral blood mononuclear cells (PBMCs) from normal goat kids (n = 8, PRNP+/+) and goat kids without PrPC (n = 8, PRNPTer/Ter) by mRNA sequencing. PBMCs normally express moderate levels of PrPC. 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 PrPC, 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 PrPC 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 PrPC physiology.