MECHANISMS OF VIRAL PATHOGENESIS

小鼠细胞内宿主的有效抗流感病毒活性

The potent anti-influenza viral activity of the murine intracellular host protein Mxl has stimulated the search for related, potentially antiviral proteins in other organisms. To date, a total of 12 related sequences nave been cloned and some of the respective proteins analyzed. The family of Mx proteins comprises members serving seemingly disparate, including non-antiviral, functions. The following subgroups can be distinguished: 1) interferon-regulated, antiviral proteins (e.g. mouse Mxl, human MxA); 2) interferon-regulated proteins devoid of antiviral activity (e.g. rat Mx3, human MxB); 3) constitutive proteins important for proper exocytotic protein trafficking (e.g. yeast Vps 1); 4) constitutive proteins important in endocytosis, particularly at the neuromuscular junction (e.g. Drosophila dynamin). Sequence analysis has revealed a high degree of conservation of the proteins' amino-terminal halves which include a tripartite consensus element characteristic of GTP-binding proteins, and a lower degree of conservation, or no conservation at all, in their carboxyl-terminal halves. A mutational analysis shows that it is this carboxyl-terminal region that is important for antiviral activity. In order to understand the role and evolution of this family of proteins, and exploit them for antiviral purposes, we need to know whether each Mx protein performs a unique function, or whether all Mx proteins perform similar functions operating through the same basic molecular mechanism. To this end, we began to test interferon-inducible rat Mx proteins for functional similarities with rat dynamin. We found that both antivirally active and inactive cytoplasmic Mx proteins share with dynamin the binding of microtubules in vitro. Furthermore, none of these proteins seems colocalized with microtubules in vivo, and they can be extracted from unfixed cells with detergent, possibly because they are membrane-associated. Thus, Mx proteins and dynamin may share functional similarities in vivo. However, the fact that both antivirally active and inactive proteins behave like dynamin suggests that the antiviral activities of Mx proteins may be dissociated from their cellular functions. A dissociation of cellular and antiviral functions is also suggested from a different set of experiments. When the cytoplasmic rat Mx2 protein--a protein lacking anti-influenza activity--was mutated such that it now accumulated in the nucleus, it became active against influenza virus. Studies are in progress to determine with which cellular structures Mx proteins associate in vivo, and how they act against viruses at the molecular level.