Structural modeling and analysis of dengue-mediated inhibition of interferon signaling pathway

B. Aslam, J. Ahmad, A. Ali, R.Z. Paracha, S.H.K. Tareen, S. Khusro, T. Ahmad, S.A. Muhammad, U. Niazi, V. Azevedo
2015 Genetics and Molecular Research  
Dengue virus (DENV) belongs to the family Flaviviridae and can cause major health problems worldwide, including dengue fever and dengue shock syndrome. DENV replicon in human cells inhibits interferon α and β with the help of its non-structural proteins. Nonstructural protein 5 (NS5) of DENV is responsible for the proteasomemediated degradation of signal transducer and activator of transcription B. Aslam et al. 4216 ©FUNPEC-RP Genetics and Molecular Research 14 (2):
more » ... ch 14 (2): 4215-4237 (2015) (STAT) 2 protein, which has been implicated in the development of resistance against interferon-mediated antiviral effect. This degradation of STAT2 primarily occurs with the help of E3 ubiquitin ligases. Seven in absentia homologue (SIAH) 2 is a host protein that can mediate the ubiquitination of proteins and is known for its interaction with NS5. In this study, comprehensive computational analysis was performed to characterize the protein-protein interactions between NS5, SIAH2, and STAT2 to gain insight into the residues and sites of interaction between these proteins. The objective of the study was to structurally characterize the NS5-STAT2, SIAH2-STAT2, and NS5-SIAH2 interactions along with the determination of the possible reaction pattern for the degradation of STAT2. Docking and physicochemical studies indicated that DENV NS5 may first interact with the host SIAH2, which can then proceed towards binding with STAT2 from the side of SIAH2. These implications are reported for the first time and require validation by wet-lab studies. Key words: Signal transducer and activator of transcription 2; Dengue virus; Non-structural protein 5; Seven in absentia homologue; Interface residues; Protein-protein interactions Protein-Protein interaction analysis of Dengue virus and host ©FUNPEC-RP Genetics and Molecular Research 14 (2): 4215-4237 (2015) phosphorylation of STAT1 and STAT2 (Darnell et al., 1994; Schindler et al., 2007) . The phosphorylated STAT1 and STAT2 subsequently translocate into the nucleus, where they transcribe various IFN responsive elements (ISRE) and induce antiviral effects against the virus (Aaronson and Horvath, 2002) (Figure 1 ). Various experimental studies in IFNAR knockout mice (KO) STAT2 KO mice have already shown the significance of interferon-dependent immune response for restriction of DENV replication (Ashour et al., 2010) .
doi:10.4238/2015.april.28.4 pmid:25966194 fatcat:t4mcwqamyzc3tezf4ln5uube5a