Herpes simplex virus-1 induces expression of a novel MxA isoform that enhances viral replication.
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.
Ku
Chia-Chi
CC
The Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Che
Xi-Bing
XB
Reichelt
Mike
M
Rajamani
Jaya
J
Schaap-Nutt
Anne
A
Huang
Ke-Jung
KJ
Sommer
Marvin H
MH
Chen
Yi-Shun
YS
Chen
Yi-Yuan
YY
Arvin
Ann M
AM
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006561:Herpes Simplex / Q000235:genetics / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000821:virology; D008969:Molecular Sequence Data; D064547:Myxovirus Resistance Proteins; D014176:Protein Biosynthesis / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014771:Virion / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D019204:GTP-Binding Proteins