The genetic driver of Acute Necrotizing Encephalopathy, RANBP2, regulates the inflammatory response to Influenza A...

Area of Science:

• Virology
• Cell Biology
• Immunology

Background:

• Influenza virus infections can lead to severe complications like Acute Necrotizing Encephalopathy (ANE).
• ANE is linked to dominant mutations in the nucleoporin RANBP2 (also known as Nup358).
• The precise role of RANBP2 in influenza-induced inflammation is not fully understood.

Purpose of the Study:

• To investigate the role of RANBP2 in influenza A virus (IAV)-triggered inflammatory responses.
• To determine how RANBP2 deficiency or specific mutations affect IAV replication and host immune signaling.

Main Methods:

• Utilized human airway epithelial cells and primary macrophages.
• Depleted RANBP2 using knockdown techniques.
• Introduced the ANE1 disease-associated RANBP2-T585M mutation using CRISPR-Cas9 gene editing.
• Assessed IAV replication, viral polymerase subunit import, vRNA export, and chemokine production.

Main Results:

• RANBP2 depletion enhanced IAV genomic replication by facilitating viral polymerase subunit import.
• RANBP2 knockdown promoted viral genomic RNA export and disrupted segment stoichiometry.
• Reduced RANBP2 levels led to increased production of pro-inflammatory chemokines (CXCL8, CXCL10, CCL2, CCL3, CCL4).
• The RANBP2-T585M mutation caused loss of RANBP2 localization at the nuclear envelope, mimicking knockdown effects on IAV replication and inflammation.

Conclusions:

• RANBP2 regulates influenza virus RNA replication and nuclear export, acting as a brake on virus-induced hyperinflammation.
• Impaired RANBP2 localization at the nuclear envelope is implicated in the pathogenesis of ANE1.
• RANBP2 is a key host factor controlling influenza virus infection outcomes and associated inflammation.