Effects of Adenovirus E1A Protein on Interferon-Signaling

Abstract

We have previously shown that adenovirus E1A proteins can block interferon-alpha (IFN-alpha)-signalling. In the current study, we examined if the same is true for IFN-gamma signaling. Cotransfection experiments showed that both 289R and 243R forms of E1A could block the expression of an IFN-gamma-inducible reporter gene. Similarly, in an E1A-expressing HeLa cell line IFN-gamma failed to induce the synthesis of IRF-1 mRNA. This failure was due to a block in activation of the crucial trans-acting factor, GAF, which in turn was due to the lack of IFN-gamma-activated tyrosine phosphorylation of the STAT1 alpha protein in E1A-expressing cells. The above defect could be attributed to a reduced level of STAT1 alpha protein. The level of p48 protein, which is required for IFN-alpha signaling, was also lowered. However, the level of lak-1 protein, one of the tyrosine kinases necessary for both IFN-alpha and IFN-gamma signalling, was comparable in the E1A-expressing and the control cells. These results indicate that the observed inhibition of IFN signalling in E1A-expressing cells is a consequence of a lower abundance of the necessary trnas-acting factors.

The Type I Interferon-α Mediates a More Severe Neurological Disease in the Absence of the Canonical Signaling Molecule Interferon Regulatory Factor 9

“…Moreover, the results here give deeper insight into our understanding of the pathogenesis of proposed neurological "interferonopathies" such as AGS and suggest that some key neuropathological changes in these disorders may arise from noncanonical signaling mediated by IFN-␣. Finally, modifications to type I IFN signaling pathways [as can occur following infection with certain viruses (Leonard and Sen, 1996;Miller et al, 1999;Palosaari et al, 2003;Zurney et al, 2009] may cause dramatic changes in the biological actions of this cytokine, including enhanced development of disease.…”

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

“…Furthermore, HBV core/precore proteins interact directly with the MxA gene promoter (Fernandez et al, 2003). The AdV E1A protein disrupts transcriptional responses to IFN-a/b and IFN-c by decreasing the levels of STAT1 and IRF-9 (Leonard & Sen, 1996), by sequestering the transcriptional co-activator CBP/p300, which binds STAT1 and STAT2 and is involved in transcription responses mediated by these proteins (Bhattacharya et al, 1996;Zhang et al, 1996), and by interacting with STAT1 directly (Look et al, 1998). Furthermore, viruses may limit long-term IFN signalling by targeting other transcription factors.…”

Polyinosinic-Polycytidylic Acid Treatment of Friend Retrovirus-Infected Mice Improves Functional Properties of Virus-Specific T Cells and Prevents Virus-Induced Disease

“…Vaccina virus encodes multiple genes that antagonize with the action of type I IFN (10). Also, other viruses like influenza A virus (11,12), rotavirus (13), rabies virus (14), Ebola virus (15), HSV type 1 (16), Epstein-Barr virus (17), hepatitis C virus (18)(19)(20)(21)(22), and adenovirus (23)(24)(25) have evolved means to downregulate the IFN response at different phases of infection. During retroviral infections, such as HIV, SIV, or Friend retro virus (FV), the type I IFN response is quite weak.…”