Although the DnaJB1-PKAc fusion protein is the driver of FL-HCC, our structures of the RIα holoenzyme and the RIIβ holoenzyme with J-C subunit do not reveal a clear mechanism for the pathogenesis of the mutation; instead, we showed that the regulation of each holoenzyme is disrupted. Here, DNAJB1 is linked to hepatocellular carcinoma.