Strain-to-strain difference of V protein of measles virus affects MDA5-mediated IFN-β-inducing potential.
Laboratory-adapted and vaccine strains of measles virus (MV) induce type I interferon (IFN) in infected cells to a far greater extent than wild-type strains. We investigated the mechanisms for this differential type I IFN production in cells infected with representative MV strains. The overexpression of the wild-type V protein suppressed melanoma differentiation-associated gene 5 (MDA5)-induced IFN-β promoter activity, while this was not seen in A549 cells expressing CD150 transfected with the V protein of the vaccine strain. The V proteins of the wild-type also suppressed poly I:C-induced IFN regulatory factor 3 (IRF-3) dimerization. The V proteins of the wild-type and vaccine strain did not affect retinoic acid-inducible gene 1 (RIG-I)- or toll-IL-1R homology domain-containing adaptor molecule 1 (TICAM-1)-induced IFN-β promoter activation. We identified an amino acid substitution of the cysteine residue at position 272 (which is conserved among paramyxoviruses) to an arginine residue in the V protein of the vaccine strain. Only the V protein possessing the 272C residue binds to MDA5. The mutation introduced into the wild-type V protein (C272R) was unable to suppress MDA5-induced IRF-3 nuclear translocation and IFN-β promoter activation as seen in the V proteins of the vaccine strain, whereas the mutation introduced in the vaccine strain V protein (R272C) was able to inhibit MDA5-induced IRF-3 and IFN-β promoter activation. The other 6 residues of the vaccine strain V sequence inconsistent with the authentic sequence of the wild-type V protein barely affected the IRF-3 nuclear translocation. These data suggested that the structural difference of laboratory-adapted [corrected] MV V protein hampers MDA5 blockade and acts as a nidus for the spread/amplification of type I IFN induction. Ultimately, measles vaccine strains have two modes of IFN-β-induction for their attenuation: V protein mutation and production of defective interference (DI) RNA.
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan.
Hiromi
H
Takaki
Yumi
Y
Watanabe
Masashi
M
Shingai
Hiroyuki
H
Oshiumi
Misako
M
Matsumoto
Tsukasa
T
Seya
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D007753:Laboratories; D008459:Measles virus / Q000276:immunology; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology*
D015703:Antigens, CD; D010750:Phosphoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C000604059:SLAMF1 protein, human; C069181:V protein, measles virus; D014764:Viral Proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D016899:Interferon-beta; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D003545:Cysteine