PARADOXICAL INTERACTIONS BETWEEN HUMAN DELTA-HEPATITIS AGENT RNA AND THE CELLULAR PROTEIN-KINASE PKR

The genome of the human delta hepatitis agent is a circular, highly st ructured single-stranded RNA lacking regular runs of RNA-RNA duplex lo nger than 15 bp. We have tested the ability of delta agent RNA to part icipate in reactions with a protein containing a motif which confers t he ability to bind double-stranded RNA (dsRNA). Surprisingly, highly p urified delta agent RNA preparations from which all traces of contamin ating dsRNA have been removed activate PKR, the dsRNA-dependent protei n kinase activity of mammalian cells (also known as DAI, P1-eIF-2, and p68 kinase). This behavior is in marked contrast to the interaction o f PKR with a number of other highly structured viral single-stranded R NAs, which inhibit, rather than stimulate, activation of this kinase. PKR activation leads to inhibition of protein synthesis in the rabbit reticulocyte lysate system. Paradoxically, delta RNA failed to elicit the expected PKR-mediated inhibition of cell-free translation. Instead , delta RNA interfered with PKR activation and the translational block induced by dsRNA. We conclude that the interaction of PKR and delta a gent RNA may represent a new category of protein-RNA interactions invo lving the dsRNA binding motif.