Thogoto virus ML protein suppresses IRF3 function

The Thogoto virus (THOV) is a member of the family Orthomyxoviridae. It prevents induction of alphabeta interferons (IFN) in cell culture and in vivo via the action of the viral ML protein. Phenotypically. the effect of THOV ML resembles that of the NSI protein of influenza A virius (FLUAV) in that it blocks the expression of IFN genes. IFN expression depends on IFN regulatory factor 3 (IRF3). Upon activation, IRF3 forms homodimers and accumulates in the nucleus where it binds the transcriptional coactivator CREB-binding protein (CBP). Here, we show that expression of ML blocked the transcriptional activity of IRF3 after stimulation by virus infection. Further biochemical analysis revealed that ML acts by blocking lRF3 dimerization and association with CBP. Surprisingly. however. ML did not interfere with the nuclear transport of IRF3. Thus. the action of ML differs strikingly front that of FLUAV NS1 that prevents IFN induction by retaining IRF3 in the cytoplasm. (C) 2004 Elsevier Inc. All rights reserved.