Hsp90 Activity Is Necessary for the Maturation of Rabies Virus Polymerase

Area of Science:

• Virology
• Molecular Biology
• Protein-protein interactions

Background:

• Mononegavirales viruses possess a non-segmented negative-strand RNA genome encoding essential viral proteins.
• Viral replication relies on a polymerase complex comprising large (L) and phosphoprotein (P) proteins.
• Heat shock protein 90 (Hsp90) chaperone activity is crucial for Mononegavirales replication, with prior studies showing L protein degradation upon Hsp90 inhibition, except for rabies virus (P protein degradation).

Purpose of the Study:

• To investigate the effect of Hsp90 inhibition on rabies virus L and P protein expression and polymerase complex formation.
• To determine the virus-specific roles of L and P proteins in polymerase maturation under Hsp90 inhibition.

Main Methods:

• Analysis of rabies virus L and P protein expression following Hsp90 inhibition.
• Assessment of L and P protein binding and functional viral polymerase assembly.
• Comparative analysis of L protein expression independence from P protein and Hsp90 inhibition across different viruses (rabies, vesicular stomatitis virus, measles virus).

Main Results:

• Hsp90 inhibition did not affect rabies virus L and P protein expression levels.
• Hsp90 inhibition impaired the binding of rabies virus L and P proteins, preventing functional viral polymerase formation.
• Rabies virus and vesicular stomatitis virus L proteins, unlike measles virus L protein, could be expressed independently of P protein and Hsp90 inhibition.

Conclusions:

• Hsp90 inhibition disrupts rabies virus polymerase assembly by preventing L and P protein interaction, rather than causing protein degradation.
• The interaction dynamics between L, P proteins, and Hsp90 during polymerase maturation appear to be virus-specific.
• These findings highlight a novel mechanism of Hsp90-mediated regulation in viral replication distinct from protein degradation pathways.