Direct Suppression of Stat1 Function during Adenoviral Infection

Abstract

The action of adenoviral E1A oncoprotein on host immune-response genes has been attributed to interaction with p300/CBP-type transcriptional coactivators in competition with endogenous transcription factors such as signal transducer and activator of transcription (STAT) proteins. However, we show that mutant forms of E1A that no longer bind p300/CBP can still interact directly with Stat1 (via E1A N-terminal and Stat1 C-terminal residues) and block IFNgamma-driven, Stat1-dependent gene activation and consequent function during early-phase infection in the natural host cell. The results provide a distinct and more specific mechanism for E1A-mediated immune suppression and an alternative model of IFNgamma-driven enhanceosome formation that may allow for other adaptors (in addition to p300/CBP) to link Stat1 to the basal transcription complex.

The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α

“…For example, E7 displays considerable structural and functional similarities to adenovirus E1A protein (Howley, 1996;Tommasino and Crawford, 1995). E1A functions as a potent suppressor of IFN signaling (Gutch and Reich, 1991;Kalvakolanu et al, 1991;Sen, 1996, 1997;Routes et al, 1996) by interacting with and impairing the transcriptional function of STAT1 (Look et al, 1998). A systematic approach to investigate the regulation of IFN signaling by the HPV oncoproteins may prove helpful to better understand the molecular basis of HPV-resistance to IFN action and may lead to the development of new strategies to combat HPVinfection and associated diseases.…”

STAT proteins: novel molecular targets for cancer drug discovery

“…Thesè pseudo-coactivators' could be engineered to possess higher a nity for Stat3 since they must compete with natural coactivator molecules. In principle, pseudocoactivators would block the biological e ects of STATs by substituting for natural coactivators and suppressing the transcriptional activities of Stat3, analogous to the block of IFN-g-Stat1-mediated gene activation and biological e ects by a mutant adenovirus E1A protein (Look et al, 1998). The competitive pseudo-coactivators could be designed taking advantage of the uniqueness of the point of interaction of these molecules with the speci®c STAT member that would allow preferential high-a nity interaction that confers speci®city.…”

Role and fate of PML nuclear bodies in response to interferon and viral infections

“…The adenovirus E1A protein disrupts the response to both IFN a/b and IFNg at the level of signal transduction by decreasing the p48 level (Leonard and Sen, 1997) and interacting directly with Stat1 (Look et al, 1998). Adenovirus produces short RNA molecules (VAI RNA) that can form a secondary structure interacting with the ds RNA-binding site on PKR and acting as a competitive inhibitor (Sharp et al, 1993).…”