HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• RIG-I (Retinoic acid-inducible protein I) is a crucial cytosolic sensor for viral RNA detection, initiating innate immune responses.
• Posttranslational modifications regulate RIG-I signaling, but their role in viral RNA sensing is not fully understood.
• Understanding RIG-I regulation is key to developing effective antiviral therapies.

Purpose of the Study:

• To investigate the role of deacetylation in regulating RIG-I's viral RNA-sensing activity.
• To identify the specific deacetylase involved and its mechanism of action.
• To assess the in vivo significance of this regulatory pathway in antiviral immunity.

Main Methods:

• Biochemical assays to study RIG-I deacetylation and binding with HDAC6.
• Analysis of RIG-I acetylation status (Lysine 909) in the presence of viral RNA.
• Gene depletion (siRNA) and knockout mouse models to assess antiviral responses.
• Infection studies with RNA and DNA viruses in wild-type and HDAC6 knockout mice.

Main Results:

• HDAC6-mediated deacetylation of RIG-I is critical for its viral RNA-sensing function.
• HDAC6 transiently binds to RIG-I and removes acetylation at Lysine 909 upon viral RNA detection.
• Depletion of HDAC6 impairs antiviral responses against RNA viruses but not DNA viruses.
• HDAC6 knockout mice exhibit increased susceptibility to RNA virus infections.

Conclusions:

• HDAC6 plays a vital role in modulating the RIG-I-mediated antiviral sensing pathway.
• HDAC6-dependent deacetylation enhances RIG-I's ability to detect viral RNA.
• This pathway is essential for effective host defense against RNA viruses.