Determining the regulation and expression of murine Ptch53 and its contribution to the innate immune response to influenza A infection
Embargo until
2023-05-01
Date
2019-02-26
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Publisher
Johns Hopkins University
Abstract
The 12-pass transmembrane receptors that are orthologous to the Drosophila Patched protein have a well-established role in developmental morphogenesis that is evolutionarily conserved. In mammals the prototypical Patched protein is encoded by the classical tumor suppressor gene PTCH1. The function of PTCH1 is to control signaling by the Hedgehog pathway; the mutational loss of this function in adult tissues causes cancer. In addition to PTCH1, mammalian genomes harbor at least six distinct genes that encode proteins with significant structural homology with the Patched family. The functions of these genes are poorly understood. This study examined a novel role of a mammalian Patched family member called PTCH53 (also known as PTCHD4). This gene is unique in the Patched family because it is highly p53-responsive. Preliminary data shows up-regulation of interferon-stimulated genes (ISGs) in response to PTCH53 overexpression. As ISGs are integral to the host anti-viral responses, this result had suggested a role for PTCH53 in innate immunity. To better understand how PTCH53 might function in the innate immune responses, a novel knockout mouse was characterized. Murine Ptch53 is highly homologous to human PTCH53, but was found to be significantly less responsive to p53. Expression of the ISG Oas1g was elevated in the Ptch53-knockout mouse lung compared with the wildtype. To determine the role of Ptch53 in the innate immune response to viral infection, we challenged male Ptch53-knockout, Trp53-knockout, and mice wildtype for both genes with a murine-adapted strain of influenza A virus (IAV). Two days following intranasal IAV administration, the Ptch53-knockout lung had significantly higher expression of Mcp1 and Ip10 than the wildtype. Furthermore, the Ptch53-knockout lung had the highest expression of IAV mRNAs in the cohort. This evidence suggests that Ptch53 is required for an effective innate immune response to IAV. Double-knockout mice (Trp53-/-/Ptch53-/-) were viable and fertile. Interestingly, the lifespans of these mice significantly exceeded the median lifespan of Trp53-knockouts, suggesting a novel interaction between these two genes. Future studies may illuminate the mechanisms by which this class of proteins can regulate ISG expression, and their interactions with p53.
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Keywords
Patched family, PTCH53, innate immunology, IAV, Influenza, PTCHD4, Hedgehog, p53, TP53, Trp53, ISG, interferon-stimulated genes, anti-viral response, mouse model