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

## TL;DR

This study identifies DNAJB12 and DNAJB14 as important proteins involved in the formation of hepatitis B and D viruses, offering new insights into potential antiviral drug targets.

## Contribution

The study reveals novel roles of DNAJB12 and DNAJB14 in HBV and HDV particle formation and identifies DNAJB12 as a target of the antiviral compound REP 2139.

## Key findings

- DNAJB12 is essential for the morphogenesis of HBV and HDV virions and is targeted by REP 2139.
- DNAJB14 is required for HBV and HDV formation but does not affect HBV spherical subviral particles.
- Knockdown of DNAJB12 and DNAJB14 impairs the production of infectious HDV.

## Abstract

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.

•DNAJB12 is crucial for the morphogenesis of HBV Dane and SVPs as well as HDV virions•DNAJB14 does not affect HBV spherical SVPs but is required for HBV and HDV formation•DNAJB12, but not DNAJB14, is targeted by REP 2139 via its domain of unknown function

DNAJB12 is crucial for the morphogenesis of HBV Dane and SVPs as well as HDV virions

DNAJB14 does not affect HBV spherical SVPs but is required for HBV and HDV formation

DNAJB12, but not DNAJB14, is targeted by REP 2139 via its domain of unknown function

Natural sciences; Biological sciences; Microbiology; Virology