Adenovirus early region 4 is essential for normal stability of late nuclear RNAs

H2dl808 is a deletion mutant of adenovirus type 2 lacking most of transcriptional early region E4. In most normal adenovirus host cells this virus displayed a complex mutant phenotype that included a dramatic reduction in the level of cytoplasmic late RNA, a corresponding defect in late protein synthesis, and a 5- to 10-fold defect in viral DNA accumulation. H5dl1004 is a deletion mutant of adenovirus type 5 that also lacks a portion of E4. It exhibited a reduction in levels of cytoplasmic late RNAs that was somewhat less severe than that of H2dl808 and a corresponding late protein synthetic defect but no defect in the production of viral DNA. In addition to the defect in the accumulation of late cytoplasmic mRNAs, HeLa cells infected by either H2dl808 or H5dl1004 showed substantially reduced levels of viral RNAs in their nuclei at late times after infection. Both mature mRNAs and apparent mRNA precursors were affected. The late transcription rates of the deletion mutant viruses were similar to that of wild-type virus. These results suggest that the underaccumulation of RNA in H2dl808- and H5dl1004-infected cells is caused by a reduction in the stability of viral RNA in the nucleus, and they implicate E4 products in a novel aspect of the regulation of viral gene expression.