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Title: A Conserved Domain in the Leader Proteinase of Foot-and-Mouth Disease Virus is Required for Proper Subcellular Localization and Function

item De Los Santos, Teresa
item Zhu, James
item Koster, Marla
item Grubman, Marvin

Submitted to: European Study Group on the Molecular Biology of Picornaviruses
Publication Type: Abstract Only
Publication Acceptance Date: 3/11/2008
Publication Date: 5/26/2008
Citation: De Los Santos, T., San Segundo-Diaz, F., Zhu, J., Koster, M.J., Grubman, M.J. 2008. A conserved domain in the leader proteinase of foot-and-mouth disease virus is required for proper subcellular localization and function. European Study Group on the Molecular Biology of Picornaviruses. P 86

Interpretive Summary:

Technical Abstract: The leader proteinase (Lpro) of foot-and-mouth disease virus (FMDV) is involved in antagonizing the innate immune response by blocking the expression of interferon (IFN) protein and by reducing the immediate-early induction of IFNß mRNA and IFN stimulated genes. Recently we have shown that expression of Lpro leads to degradation of the p65/RelA subunit of the transcription factor NF'B. Upon infection with wild type (wt) FMDV, p65/RelA translocates and accumulates in the nucleus of the cell but with the course of infection this signal progressively disappears correlating with an increase in expression and nuclear localization of viral Lpro. This effect is specific since infection with a genetically engineered virus lacking the Lpro coding region (leaderless) resulted in accumulation of p65/RelA in the nucleus. We have performed microarray analysis and found that the expression of several NF'B dependent genes is significantly higher in leaderless than in wt FMDV infected cells. Bioinformatics analysis of the Lpro protein sequence and its 3D structure, suggested that this protein contains a putative DNA-binding motif found in nuclear scaffold attachment factors and some signaling proteins such as protein inhibitor of activated STAT (PIAS) among others. We have mutated conserved Lpro residues within this domain and recovered stable mutant viruses. These viruses displayed small plaque phenotype and grew to lower titers suggesting an attenuated phenotype. Indirect immunofluorescence analysis showed an altered Lpro sub-cellular distribution in cells infected with the mutant FMDV. Whereas wild type Lpro accumulated in the nucleus, mutant Lpro was only detected in the cytoplasm of infected cells by 5 hours post infection. Interestingly nuclear p65/RelA staining disappeared from wt but not from mutant virus infected cells. We are currently characterizing these mutants in more detail to better understand the molecular mechanisms employed by FMDV to evade the immune response