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The interferon induced transmembrane protein 1 (Ifitm1): detailed analysis on its assumed functions

ABSTRACT: Several functions have been suggested for the interferon induced transmembrane protein 1 (Iftitm1) gene in mammals. Originally it was identified as a member of a gene family that is highly inducible by type I and type II inteferons. Based on its expression during primordial germ CELl (PGC) specification it was suggested to be required for normal PGC migration. Ifitm1 targeted knockdown experiments in mouse embryos provided evidence that the gene might be necessary for normal somitogenesis. Finally, the complete deletion of the Ifitm gene cluster on mouse chromosome 7 revealed that the five deleted Ifitm1 genes are not essential for PCG migration and fertility. Here, we generated a novel targeted knockin allele of the Ifitm1 gene by replacing its coding region with a lacZ reporter gene to systematically reassess the suggested functions of this gene. We find that during embryogenesis somites and in the adult the vertebral column appear normal in homozygous Ifitm1 knockout mice, strongly suggesting that Ifitm1 is not essential for normal segmentation of the paraxial mesoderm. In addition, homozygous Ifitm1 mutant mice are fertile, reproduce normally and have normal sperm quality. Furthermore, we show that the Ifitm1 loss-of-function allele does not cause immunological mutant phenotypes in unchallenged as well as in Listeria challenged homozygous mutant animals. To further focus on unique functional requirements of Ifitm1, we took advantage of the lacZ reporter gene in the Ifitm1 locus to analyze for the first time in detail and with high sensitivity its complex expression pattern in mouse embryos from E8.5 to E14.5 and in adult organs. The detailed description of the Ifitm1 expression domains will support the identification of organs that might be affected by the loss of Ifitm1 function.

ORGANISM(S): Mus musculus

PROVIDER: GSE24744 | GEO | 2012/08/06

SECONDARY ACCESSION(S): PRJNA132139

REPOSITORIES: GEO

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Project description:Interferon-induced transmembrane protein (IFITM1) plays a dual role in restriction of RNA viruses and in metastatic cancer cell growth. The signal transduction events that are orchestrated by IFITM1 are not well defined. We set out to identify IFITM1 interacting proteins to begin to define its mechanism of action. Affinity purification of SBP-tagged IFITM1, coupled to SWATH-mass spectrometry, identified significantly higher confidence interacting proteins from IFN- treated cells, relative to non-treated cells. This promoted an examination of the protein synthetic machinery in order to determine whether IFITM1 can impact on ribosomal proteome from IFN- treated cells. Isogenic ifitm1 null and ifitm1-ifitm3 null-SiHa cell panels were generated using CRISPR gRNAs to define signaling events that are linked to IFN--dependent protein synthesis. Ultracentrifugation sedimentation of cell lysates from interferon gamma treated wt and ifitm1-ifitm3 null-SiHa cells was carried out to isolate ribosomal constituents. Although SWATH-mass spectrometry of the 40S, 60S, and 80S fractions demonstrated changes in selected protein content, a significant reduction in A254 (RNA) in the 80S ribosomal fractions suggested a relatively select defect in 80S ribosomal biogenesis in ifitm1-ifitm3 null cells. The localization of IFITM1 to ribosomal protein components prompted an analysis of IFN--dependent protein synthesis using pulse SILAC. STAT1 and B2M were two dominant proteins whose synthesis increased equivalently in wt or ifitm1-ifitm3 null cells. However, MHC class I molecules and ISG15 were the most highly suppressed IFN--responsive proteins in the ifitm1-ifitm3 double null cells and this was confirmed using ifitm1 single null cells. Transient depletion of IFITM1 using targeted siRNA also depleted MHC class I molecules as well as IFITM3, STAT1, B2M, and ISG15. These data have implications for the function of IFITM1 in mediating IFN--stimulated protein synthesis and associated antigen presentation during either oncogenic or anti-viral signalling.

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The interferon induced transmembrane protein 1 (Ifitm1): detailed analysis on its assumed functions

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