Control of Apoptosis by Human Adenovirus Genes

Abstract

Adenovirus infection induces apoptosis by multiple paradigms that involve viral proteins coded by three different early gene regions,E1A, E3,andE4.These cell death programs are antagonized by a different set of viral proteins coded by early gene blocksE1B, E3,andE4.The E1A proteins activate the cellular transcription factor E2F and also increase accumulation of the p53 tumor suppressor protein, both proteins with known apoptotic activity. The E1B-19K protein, a distantly related member of the BCL-2 family of antiapoptosis proteins, efficiently suppresses both p53-dependent and -independent apoptosis induced during adenovirus infection. Two other proteins, E1B-55K and E4-36K, which inactivate p53 by physical protein complex formation suppress p53-dependent apoptosis. The mechanisms by which the E1B-19K protein acts are not fully known, but at least one appears to involve antagonizing the activity of various cellular pro-apoptotic proteins such as BAX, BAK, and BIK. One of the two major E1A proteins, 289R, also appears to induce cell death via transactivation of the cellular transcription factor NF-κB as well as two early gene blocks,E3andE4.NF-κB is believed to induce expression of TNF and various inflammatory cytokines in virus-infected cells. TheE3andE4gene blocks each code for a cell death protein, E3-11.6K (ADP) and E4-orf4. The E1A proteins also sensitize infected cells for TNF-induced apoptosis and this activity is linked to the cell cycle regulatory activities of E1A. In addition to the E1B-19K protein, three E3 proteins, 14.7K, 10.4K, and 14.5K, specifically protect cells against TNF-induced cell death. One of the mechanisms by which the E3-14.7K and E3-10.4K/14.5K complex suppress TNF-induced toxicity appears to be mediated by the release of arachidonic acid by the cytosolic phospholipase A2. The E3 proteins also inhibit Fas-agonist-induced apoptosis by endosome-mediated internalization and degradation of Fas from the cell surface. Suppression of E1A-induced apoptosis in nonpermissive cells by E1B-19K, E1B-55K, and E4-36K proteins leads to oncogenic transformation.