Disease relevance of Mx1

• Human cells treated with interferon synthesize two proteins that exhibit high homology to murine Mx1 protein, which has previously been identified as the mediator of interferon-induced cellular resistance of mouse cells against influenza viruses [1].
• BALB/3T3 fibroblasts expressing stably Mx2 but not Mx1 had an antiviral activity against recombinant vesicular stomatitis virus (VSV) [2].
• Mx is an interferon (IFN)-inducible intracellular protein found in various vertebrates that mediates resistance against negative-strand RNA viruses [3].
• The polymeric form of Mx1 from E. coli was observed as "horseshoe"-like structure by negative staining microscopy [4].
• Moreover, stable lines of transfected mouse 3T3 cells that constitutively express Mx1 protein showed increased resistance to Thogoto virus infection [5].

High impact information on Mx1

• Mx protein: constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus [6].
• The predicted amino acid sequence includes a guanine nucleotide-binding domain that is homologous with those of a family of antiviral factors, inducible by interferon and known as Mx proteins, and with the product of the essential yeast vacuolar protein sorting gene VPS1 [7].
• Thus, inborn resistance of radiation chimeras was found to be independent of Mx-gene expression in cells of the hemopoietic system [8].
• Mice homozygous (A2G) or heterozygous (F1 hybrids between A2G and several susceptible strains) for the gene Mx, shown previously to induce a high level of resistance towards lethal challenge by a number of myxoviruses in vivo, yielded peritoneal macrophages which were not affected by M-TUR [9].
• Here, we show that overexpression of PML, but not that of Mx1 or MxA, leads to a drastic decrease of a complex retrovirus, the human foamy virus (HFV), gene expression [10].

Biological context of Mx1

• It consists of 14 exons, greatly homologous to the Mx1 gene [3].
• The mouse genome contains two related interferon-regulated genes, designated Mx1 and Mx2 [11].
• These conserved sequences are also present in a double-stranded RNA-inducible fish gene, which suggests that they may constitute a functionally important domain of Mx proteins [1].
• Interferon-inducible Mx gene expression in cotton rats: cloning, characterization, and expression during influenza viral infection [12].
• Cytoplasmic Mx1(E614), which differs from wild-type Mx1 by a single amino acid substitution in its nuclear transport signal, failed to inhibit the multiplication of influenza virus and vesicular stomatitis virus [13].

Anatomical context of Mx1

• In contrast to the cases of mouse Mx1 and human Mx proteins, permanent cell lines were extremely unstable with respect to Mx2 expression [11].
• Expression of the repaired Mx2 cDNA in Swiss mouse 3T3 cells gave rise to an 80-kDa cytoplasmic protein that cross-reacted with antibodies to other Mx proteins [11].
• The Mx1 resistance phenotype was expressed in cultured peritoneal macrophages and interferon-treated embryonic cells obtained from these mice [14].
• The antiviral activity of mutant Mx1 proteins was analyzed by a transient transfection/influenza A infection assay in COS cells by indirect immunofluorescence [15].
• RT-PCR and immunofluorescence staining demonstrated that the Mx1 transcripts and proteins were induced by IFN-alpha/beta in macrophages from wild mouse species [16].

Associations of Mx1 with chemical compounds

• The Mx- phenotype of the Mx RFLP type 3 strain CBA/J is due to a point mutation that converts the lysine codon in position 389 to a termination codon [17].
• As analyzed, by filter binding assay, Mx1 protein (at 1 microM) showed a relatively high affinity for GDP (Kd = 1.0 x 10(-7) M) and approximately 340-fold lower affinity for guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) (Kd = 3.4 x 10(-5) M) [18].
• The antiviral activity may be mediated in part by 2',5'-oligoadenylate synthetase, RNA-dependent protein kinase, and Mx protein, which inhibit viral replication or degrade viral components, because limitin induced their mRNA expression and enzyme activity [19].
• Molecular cloning of double-stranded RNA inducible Mx genes from Atlantic salmon (Salmo salar L.) [20].
• In this work Mx genes in Atlantic salmon were studied using the double stranded RNA, polyinosinic: polycytidylic acid (poly I:C), to induce interferon production [20].

Regulatory relationships of Mx1

• Synthesis of the immunoprecipitable 75,000-dalton protein Mx was induced by interferon-alpha/beta but not by interferon-gamma in Mx+ cells of diverse genetic backgrounds [21].

Other interactions of Mx1

• We isolated clones of the transcripts of a second Mx gene (Mx2) which is closely linked to the well-characterized resistance gene and determined their sequences [22].
• In particular, PKR, RNase L, and Mx are considered to be the principal proteins through which IFNs mount an antiviral state [23].
• Furthermore, our results indicate the existence of an interferon-mediated antipoxvirus pathway that operates independently of PKR, Mx1, or the 2-5A/RNase L system [24].
• In appropriate backcross mice, no linkage was observed between Mx and md, a marker previously mapped close to the centromere of chromosome 16, suggesting a more distal localization of Mx [25].
• Since the Mx1 promoter is IFN-alpha/beta specific and the Mx1 gene is not inducible directly by IFN-gamma, these data suggest a role of IFN-alpha/beta in the host response to Salmonella infection [26].

Analytical, diagnostic and therapeutic context of Mx1

• Analysis of the subcellular localization of Mx1 and some of these interacting proteins by confocal microscopy revealed a close spatial association of Mx1 with PML NBs [27].
• Expression of the interferon (IFN)-inducible gene Mx1 and other genes was quantified using real-time polymerase chain reaction, and cytokine production was measured by enzyme-linked immunosorbent assay [28].
• The Mx1 protein purified from both mouse liver and Mx1-cDNA expressing E. coli was found to exist as assembled polymeric states judged from gel filtration pattern [4].
• Immunofluorescence analysis revealed that the nuclear localization of Mx1 and PB2 overlapped to a great extent [29].
• The PCR-RFLV and sequence analysis allowed us to classify the Mx1+ alleles of the laboratory and wild-origin mouse strains into distinct classes [16].

References