Inhibition of double-stranded RNA- and tumor necrosis factor alpha-mediated apoptosis by tetratricopeptide repeat protein and cochaperone P58(IPK)

p58(IPK) is a tetratricopeptide repeat-containing cochaperone that is invol ved in stress-activated cellular pathways and that inhibits the activity of protein kinase PKR, a primary mediator of the antiviral and antiproliferat ive properties of interferon. To gain better insight into the molecular act ions of p58(IPK). We generated NIH 3T3 cell lines expressing either wild-ty pe p58(IPK) or a p58IPK deletion mutant, Delta TPR6, that does not bind to or inhibit PKR. When treated with double-stranded RNA (dsRNA), Delta TPR6-e xpressing cells exhibited a significant increase in eukaryotic initiation f actor 2 alpha phosphorylation and NF-kappa B activation, indicating a funct ional PKR. In contrast, both of these PKR-dependent events were blocked by the overexpression of wild-type p58(IPK). In addition, the p58(IPK) cell li ne, but not the Delta TPR6 cell line, was resistant to dsRNA-induced apopto sis. Together, these findings demonstrate that p58(IPK) regulates dsRNA sig naling pathways by inhibiting multiple PKR-dependent functions. In contrast , both the p58(IPK) and Delta TPR6 cell lines were resistant to tumor necro sis factor alpha-induced apoptosis, suggesting that p58(IPK) may function a s a more general suppressor of programmed cell death independently of its P KR-inhibitory properties. In accordance with this hypothesis, although PKR remained active in Delta TPR6-expressing cells, the Delta TPR6 cell line di splayed a transformed phenotype and was tumorigenic in nude mice. Thus, the antiapoptotic function of P58(IPK) may be an important factor in its abili ty to malignantly transform cells.