Human/bovine chimeric MxA-like GTPases reveal a contribution of N-terminal domains to the magnitude of anti-influenza A activity.
Type I interferons (IFN-α/β) provide powerful and universal innate intracellular defense mechanisms against viruses. Among the antiviral effectors induced by IFN-α/β, Mx proteins of some species appear as key components of defense against influenza A viruses. The body of work published to date suggests that to exert anti-influenza activity, an Mx protein should possess a GTP-binding site, structural bases allowing multimerisation, and a specific C-terminal GTPase effector domain (GED). Both the human MxA and bovine Mx1 proteins meet these minimal requirements, but the bovine protein is more active against influenza viruses. Here, we measured the anti-influenza activity exerted by 2 human/bovine chimeric Mx proteins. We show that substituting the bovine GED for the human one in human MxA does not affect the magnitude of anti-influenza activity. Strikingly, however, substituting the human GED for the bovine one in bovine Mx1 yields a chimeric protein with a much higher anti-influenza activity than the human protein. We conclude, in contradiction to the hypothesis currently in vogue in the literature, that the GED is not the sole determinant controlling the magnitude of the anti-influenza activity exercised by an Mx protein that can bind GTP and multimerise. Our results suggest that 1 or several motifs that remain to be discovered, located N-terminally with regard to the GED, may interact with a viral component or a cellular factor so as to alter the viral cycle. Identifying, in the N-terminal portion of bovine Mx1, the motif(s) responsible for its higher anti-influenza activity could contribute to the development of new anti-influenza molecules.
Department of Pathology, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
Mutien-Marie
MM
Garigliany
Anne
A
Cornet
Daniel
D
Desmecht
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D002417:Cattle; D002522:Chlorocebus aethiops; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D008969:Molecular Sequence Data; D064547:Myxovirus Resistance Proteins; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014709:Vero Cells
D000998:Antiviral Agents; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D011994:Recombinant Proteins; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins