Abstract
MxA is an antiviral protein induced by interferon (IFN)-α/β that is known to inhibit the replication of many RNA viruses. In these experiments, the 76-kDa MxA protein expressed in IFN-α-treated cells was shown to have antiviral activity against herpes simplex virus-1 (HSV-1), a human DNA virus. However, MxA was expressed as a 56-kDa protein in HSV-1-infected cells in the absence of IFN-α. This previously unrecognized MxA isoform was produced from an alternatively spliced MxA transcript that had a deletion of Exons 14-16 and a frame shift altering the C-terminus. The variant MxA (varMxA) isoform was associated with HSV-1 regulatory proteins and virions in nuclear replication compartments. varMxA expression enhanced HSV-1 infection as shown by a reduction in infectious virus titers from cells in which MxA had been inhibited by RNA interference and by an increase in HSV-1 titers when the 56-kDa varMxA was expressed constitutively. Thus, the human MxA gene encodes two MxA isoforms, which are expressed differentially depending on whether the stimulus is IFN-α or HSV-1. These findings show that alternative splicing of cellular mRNA can result in expression of a novel isoform of a host defense gene that supports instead of restricting viral infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing / drug effects
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Alternative Splicing / genetics
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Amino Acid Sequence
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Animals
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Base Sequence
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Cell Line
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Cell Nucleus / drug effects
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Cell Nucleus / virology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / ultrastructure
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Fibroblasts / virology
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / genetics*
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GTP-Binding Proteins / metabolism
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Herpes Simplex / genetics
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Herpes Simplex / virology
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Herpesvirus 1, Human / drug effects
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Herpesvirus 1, Human / physiology*
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Herpesvirus 1, Human / ultrastructure
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Humans
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Interferon-alpha / pharmacology
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Intracellular Space / drug effects
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Intracellular Space / virology
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Molecular Sequence Data
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Myxovirus Resistance Proteins
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Protein Biosynthesis / drug effects
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Structure, Tertiary
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Protein Transport / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transcription, Genetic / drug effects
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Virion / drug effects
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Virion / physiology
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Virus Replication / drug effects
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Virus Replication / physiology*
Substances
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Interferon-alpha
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MX1 protein, human
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Myxovirus Resistance Proteins
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Protein Isoforms
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RNA, Messenger
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GTP-Binding Proteins