Unveiling DNAJB12 and DNAJB14 as crucial chaperones in hepatitis B and D virus particle morphogenesis.

During chronic HBV infection, the massive secretion of HBV envelope proteins (HBsAg) as non-infectious subviral particles (SVPs) remains a significant challenge in achieving a functional cure. Despite this, the HBsAg folding process, essential for HBV and HDV particle morphogenesis, remains poorly understood. DNAJB12 and DNAJB14 are two recently identified co-chaperones implicated in transmembrane protein folding. Utilizing the nucleic acid polymer REP 2139 as a bait, we identified DNAJB12 as a REP 2139 interactor, and its knockdown impedes the morphogenesis and secretion of SVP and HBV virions. Conversely, DNAJB14, which did not interact with REP 2139, selectively impaired the morphogenesis of virions. Additionally, knockdowns of DNAJB12 and DNAJB14 hindered the production of infectious HDV. As DNAJB12 knockdown recapitulated REP 2139 antiviral effects observed in clinical trials, our findings highlight DNAJB12 as the potential primary target of REP 2139 and uncover functional roles for DNAJB12 and DNAJB14 in HBV and HDV life cycles.