The E1B 19,000-molecular-weight protein of group C adenoviruses prevents tumor necrosis factor cytolysis of human cells but not of mouse cells

Abstract

Tumor necrosis factor (TNF) is a multifunctional immunoregulatory protein that is secreted by activated macrophages and is believed to have antiviral activities. We reported earlier that when mouse C3HA fibroblasts are infected with human adenoviruses, the 289R and 243R proteins encoded by region ElA render the cells susceptible to lysis by TNF, and a 14,700-molecular-weight protein (14.7K protein) encoded by region E3 protects the cells against lysis by TNF. We now report that the 19,000-molecular-weight (19K) (176R) protein encoded by the E1B transcription unit can protect human HEL-299 fibroblasts and human ME-180 cervical carcinoma cells against lysis by TNF. This was determined by infecting cells with adenovirus double mutants that lack region E3 and do or do not express the ElB-19K protein and by measuring cytolysis by using a short-term (18-h)-5Cr-release assay. Under these assay conditions, the-5Cr release was specific to TNF and was not a consequence of the cyt phenotype associated with ElB-19K protein-negative mutants. Also, by using virus double mutants that lack E3 in combination with other early regions, we found that ElA, the ElB-55K protein-encoding gene, E3, and E4 are not required to protect HEL-299 cells against TNF cytolysis. Three additional human cancer cell lines (HeLa, HCT8, and RC29) and a simian virus 40-transformed W138 cell line (VA-13) also required E1B for protection against TNF cytolysis, indicating that the ElB-19K protein is required to protect many if not all human cell types against lysis by TNF when infected by adenovirus. The ElB-19K protein was not able to protect six different adenovirus-infected mouse cell lines against TNF lysis, even though the protein was shown to be efficiently expressed in one of the cell lines. HEL-299 or ME-180 cells infected by a mutant that lacks the ElB-19K protein but retains region E3 were not lysed by TNF, indicating that one or more of the E3 proteins can protect these cells against TNF lysis in the absence of the ElB-19K protein. Thus, the E3-14.7K but not the EIB-19K protein can protect adenovirus-infected mouse cells against TNF cytolysis, whereas the ElB-19K protein as well as one or more of the E3 proteins can protect adenovirus-infected human cells against TNF cytolysis.

Direct interaction of hepatitis C virus core protein with the cellular lymphotoxin-beta receptor modulates the signal pathway of the lymphotoxin-beta receptor

“…The E1A protein can trigger apoptosis by repressing the transcription of genes that are required for sustained cell growth (22), and the E1B proteins (19 and 55 kDa) counteract apoptosis by stimulating expression of a subset of these cellular genes (22,72,83). The E1A protein also renders cells susceptible to lysis by the inflammatory cytokine TNF (17,25); nevertheless, this TNF-induced cytolysis is inhibited independently by the E1B 19-kDa protein and several E3 proteins to allow virus replication (24,28,29,46,91).…”

The Retinoblastoma Protein: A Master Regulator of Cell Cycle, Differentiation and Apoptosis

“…Consistent with that, cyclin-D1-induced apoptosis is dependent on its ability to bind and activate Cdk4/6 and is abrogated by coexpression of p16, a known inhibitor of cyclin-D-dependent kinases (Serrano et al, 1993). Moreover, coexpression of pRb with cyclin D1 efficiently inhibits apoptosis as also do E1B (19 kDa) and Bcl-2, both inhibitors of apoptosis (Gooding et al, 1991;Hashimoto et al, 1991;White et al, 1992;Rao et al, 1992;Hong Wang and Millner, 1996). In view of these results, it was of no surprise that, besides p16, another cyclin-dependent kinase inhibitor, p21, blocked apoptosis during myocyte differentiation (Wang and Walsh, 1996), and antisense oligonucleotides to p21 were shown to enhance cell death in differentiating neuroblastoma cells (Poluha et al, 1996).…”

“…The link between inactivation or loss of the Rbl gene and tumourigenesis prompted its classification as a tumour suppressor gene. In keeping with this, introduction of a wild-type Rbl gene into cells lacking functional pRb suppressed cell growth and tumourigenicity Bookstein et al, 1990;Takahashi et al, 1991 ;Goodrich et al, 1991 ;Qin et al, 1992), whereas antisense-mediated pRb knockout increased cell division in primary human fibroblasts (Strauss et al, 1992). The mechanism by which pRb acts as a tumour suppressor and its function in the normal cell cycle control originates from investigations unraveling the mechanism of how oncoviral proteins function to deregulate cell cycle control.…”

Oncogenicity of human papillomavirus- or adenovirus-transformed cells correlates with resistance to lysis by natural killer cells

“…This cytolytic resistance may allow for the replication and spread of Ad prior to local IFN production and concomitant acquisition of an effective NK cell response. This mechanism may complement other strategies attributed to Ad that undermine the antiviral immune response of humans (1,6,27,28,37).…”