Biology Reference
In-Depth Information
Fig. 1
Induction of IFNβ and ISG expression by CMV. Virus entry triggers the activation of
NFκB and IRF3 by way of TLRs (NFκB) and an unknown pattern recognition receptor (IRF3).
Following association with other proteins these transcription factors accumulate in the nucleus
and bind to promoter elements upstream of IFNβ and specific ISGs, thereby stimulating their
expression. HCMV IE2 is known to block binding of NFκB to DNA, while RhCMV has been
shown to block IRF3 activation via and unknown mechanism. Expression and secretion of IFNβ
further induces expression of ISGs by binding to the IFN receptor, which leads to dimerization of
the receptor subunits 1 and 2, resulting in phosphorylation of tyrosine kinase 2 (Tyk2) and Janus
kinase 1 (JAK). Tyk2 and JAK phosphorylate signal transducer and activator of transcription
(STAT) 2. STAT2 phosphorylation leads to its heterodimerization with STAT1 followed by
nuclear accumulation and association with IFN regulatory factor 9 (IRF9). This complex (termed
IFN-stimulated gene factor 3; ISGF3) binds to IFN stimulated response elements (ISREs)
upstream of numerous ISGs. Both the MCMV M27 protein and HCMV IE1 protein have been
shown to impair DNA binding of this complex
CMV Interference with the Induction of IFN and ISGs
Despite their antiviral effects, HCMV infection strikingly activates IRF3 and
NFκB, thus inducing ISGs and IFN (see the chapter by M.K. Isaacson et al., this
volume). However, infections performed in the absence of viral gene expres-
sion induce these genes more strongly (Browne et al. 2001; Taylor and
Bresnahan 2005; DeFilippis et al. 2006). Yet even UV-inactivated virus does
