Abstract
ABCF1 is an ABC transporter family protein that has been shown to regulate innate immune response and is a risk gene for autoimmune pancreatitis and arthritis. Unlike other members of ABC transporter family, ABCF1 lacks trans-membrane domains and is thought to function in translation initiation through an interaction with eukaryotic translation initiation factor 2 (eIF2). To study ABCF1 expression and function in development and disease, we used a single gene trap insertion in the Abcf1 gene in murine embryonic stem cells (ES cells) that allowed lineage tracing of the endogenous Abcf1 promoter by following the expression of a β-galactosidase reporter gene. From the ES cells, heterozygous mice (Abcf1+/-) were produced. No live born Abcf1-/- progeny were ever generated, and the lethality was not mouse strain-specific. Thus, we have determined that Abcf1 is an essential gene in development. Abcf1-/- mice were found to be embryonic lethal at 3.5 days post coitum (dpc), while Abcf1+/- mice appeared developmentally normal. Abcf1+/- mice were fertile and showed no significant differences in their anatomy when compared with their wild type littermates. The Abcf1 promoter was found to be active in all organs in adult mice, but varies in levels of expression in specific cell types within tissues. Furthermore, we observed high promoter activity in the blastocysts and embryos. Overall, Abcf1 expression in embryos is required for development and its expression in adults was highly correlated with actively proliferating and differentiating cell types.
Highlights
The ATP binding cassette (ABC) super-family of proteins are present in all phyla and harness the energy from the hydrolysis of ATP in order to transport substrates across cellular membranes and power cellular machinery [1, 2]
ABCF1 was initially identified as a protein that was up-regulated in synoviocytes in the presence of TNFα in patients with rheumatoid arthritis [4]
ABCF1 has been shown to be a key regulator of the DNA sensing pathway and regulates cytosolic DNA and retroviral infection though its exact molecular function remains unknown[5]
Summary
The ATP binding cassette (ABC) super-family of proteins are present in all phyla and harness the energy from the hydrolysis of ATP in order to transport substrates across cellular membranes and power cellular machinery [1, 2]. Members of the ABC super-family can be grouped into three categories: importers, exporters, or the third category, which are involved in DNA repair and translation and lack trans-membrane domains [1]. GCN2 is a protein kinase, which is activated by binding to uncharged tRNA [7]. GCN2 phosphorylates the eukaryotic initiation factor 2 α subunit (eIF2a), reducing protein synthesis in times of amino acid starvation [9]. This process regulates protein synthesis by coupling the availability of amino acids to the control of eIF2α by GCN2 [7]. The N-terminal sequence of GCN20 is responsible for binding to GCN1 and complementing the function of GCN2, indicating that ABCF1 has a function that is distinct from that of GCN20 [7, 11]
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