Filovirus VP24 Proteins Differentially Regulate RIG-I and MDA5-Dependent Type I and III Interferon Promoter Activation.
Felix B He, Hira Khan, Moona Huttunen, Pekka Kolehmainen, Krister Melén, Sari Maljanen, Mengmeng Qu, Miao Jiang, Laura Kakkola, Ilkka Julkunen
Author Information
Felix B He: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Hira Khan: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Moona Huttunen: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Pekka Kolehmainen: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Krister Melén: Expert Microbiology Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.
Sari Maljanen: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Mengmeng Qu: Research Center for Clinical & Translational Medicine, Fifth Medical Center for General Hospital of People's Liberation Army (PLA), Beijing, China.
Miao Jiang: Expert Microbiology Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.
Laura Kakkola: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Ilkka Julkunen: Institute of Biomedicine/Virology, University of Turku, Turku, Finland.
Filovirus family consists of highly pathogenic viruses that have caused fatal outbreaks especially in many African countries. Previously, research focus has been on Ebola, Sudan and Marburg viruses leaving other filoviruses less well studied. filoviruses, in general, pose a significant global threat since they are highly virulent and potentially transmissible between humans causing sporadic infections and local or widespread epidemics. filoviruses have the ability to downregulate innate immunity, and especially viral protein 24 (VP24), VP35 and VP40 have variably been shown to interfere with interferon (IFN) gene expression and signaling. Here we systematically analyzed the ability of VP24 proteins of nine Filovirus family members to interfere with retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated antigen 5 (MDA5) induced IFN-β and IFN-λ1 promoter activation. All VP24 proteins were localized both in the cell cytoplasm and nucleus in variable amounts. VP24 proteins of Zaire and Sudanebolaviruses, Lloviu, Taï Forest, Reston, Marburg and Bundibugyo viruses (EBOV, SUDV, LLOV, TAFV, RESTV, MARV and BDBV, respectively) were found to inhibit both RIG-I and MDA5 stimulated IFN-β and IFN-λ1 promoter activation. The inhibition takes place downstream of interferon regulatory factor 3 phosphorylation suggesting the inhibition to occur in the nucleus. VP24 proteins of Mengla (MLAV) or Bombali viruses (BOMV) did not inhibit IFN-β or IFN-λ1 promoter activation. Six ebolavirus VP24s and LloviuVP24 bound tightly, whereas MARV and MLAV VP24s bound weakly, to importin α5, the subtype that regulates the nuclear import of STAT complexes. MARV and MLAVVP24 binding to importin α5 was very weak. Our data provides new information on the innate immune inhibitory mechanisms of FilovirusVP24 proteins, which may contribute to the pathogenesis of Filovirus infections.
