Large isoform of hepatitis delta antigen activates serum response factor-associated transcription

Hepatitis delta virus infection sometimes causes severe and fulminant hepat itis as a coinfection or superinfection along with the hepatitis B virus. T o elucidate the underlying mechanism of injury caused by hepatitis delta vi rus, we examined whether two isoforms of the hepatitis delta antigen (HDAg) had any effect on five well defined intracellular signal transduction path ways: serum response factor (SRF)-, serum response element (SRE)-, nuclear factor kappaB-, activator protein 1-, and cyclic AMP response element-depen dent pathways. Reporter assays revealed that large HDAg (LIDDAg) activated the SRF- and SRE-dependent pathways. In contrast, small HDAg (LHDAg) did no t activate any of five pathways. LHDAg enhanced the transcriptional ability of SRF without changing its DNA binding affinity in an electrophoretic mob ility shift assay. In addition, LHDAg activated a rat SM22 alpha promoter c ontaining SRF binding site and a human c-fos promoter containing SRE. In co nclusion, LHDAg, but not SHDAg, enhances SRF-associated transcriptions. Des pite structural similarities be tween the two HDAgs, there are significant differences in their effects on intracellular signal transduction pathways. These results may provide clues that will aid in the clarification of func tional differences between LHDAg and SHDAg and the pathogenesis of delta he patitis.