BAG3, a host cochaperone, facilitates varicella-zoster virus replication

Area of Science:

• Virology
• Molecular Biology
• Cellular Biology

Background:

• Varicella-zoster virus (VZV) establishes lifelong latent infections.
• During latency, VZV regulatory proteins like ORF29p are present but excluded from the nucleus.
• ORF29p is a single-stranded DNA binding protein associated with VZV latency.

Purpose of the Study:

• To identify host cell proteins interacting with the VZV latency-associated protein ORF29p.
• To investigate the role of identified host proteins in VZV replication.
• To explore therapeutic strategies targeting host-pathogen interactions in VZV infection.

Main Methods:

• Protein-protein interaction studies to identify ORF29p interacting partners.
• Immunofluorescence microscopy to visualize protein colocalization during VZV lytic replication.
• RNA interference (RNAi) to deplete BAG3 expression.
• Pharmacological inhibition of Hsp90 using ansamycin antibiotics.
• Complementation assays in BAG3-depleted cells.

Main Results:

• BAG3 was identified as a host protein interacting with VZV ORF29p.
• BAG3, Hsp70/Hsc70, and Hsp90 colocalize with ORF29p in nuclear replication factories during VZV lytic phase.
• Inhibition of Hsp90 activity or depletion of BAG3 significantly inhibited VZV replication.
• Restoration of VZV replication was observed upon reintroduction of BAG3 in depleted cells.

Conclusions:

• BAG3 is a crucial host factor for VZV replication, interacting with the latency protein ORF29p.
• Host chaperone machinery, including BAG3 and Hsp90, plays a vital role in VZV lytic replication.
• Targeting host chaperone activity represents a potential novel therapeutic approach for controlling VZV infections.